ORCID Profile
0000-0002-7086-4096
Current Organisations
Maurice Wilkins Centre
,
The University of Auckland
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Publisher: Elsevier BV
Date: 07-2012
Publisher: Elsevier BV
Date: 04-1996
Publisher: Elsevier BV
Date: 09-1993
Publisher: Elsevier BV
Date: 04-1998
Publisher: Wiley
Date: 28-03-2023
Abstract: Azide‐enolate cycloaddition‐rearrangements offer potential for rapid access to erse molecular frameworks from simple precursors. We report here that investigations into the cycloadditions of ester or amide enolates with vinyl azides led to the identification of two reaction processes – direct α‐amination of amides and lactams, and the synthesis of ene‐γ‐lactams from esters. The outcomes of these reactions depended on the fate of key vinyl triazoline intermediates generated in the initial cycloaddition step. Isolation of reaction intermediates in the ene‐γ‐lactam synthesis revealed the unexpected addition of two enolate equivalents, one of which is later eliminated. Computational studies further suggested an unusual reaction pathway involving direct addition of an enolate to the terminal carbon of the N‐ vinyl triazoline. In contrast, the α‐amination of amides and lactams proceeded by rearrangement of the intermediate triazoline to give an imine, hydrolysis or reduction of which gave access to primary or secondary α‐amino amides or lactams.
Publisher: International Union of Crystallography (IUCr)
Date: 26-06-2010
Publisher: Wiley
Date: 03-09-2020
Publisher: Wiley
Date: 02-02-2022
Abstract: The number of donor atoms available on peptides that can competitively coordinate to metal centers renders the site‐selective generation of advanced metal‐peptide conjugates in high purity a challenging venture. Herein, we present a transmetalation‐based synthetic approach on solid support in which an imidazolium pro‐ligand can be used to selectively anchor a range of transition metal half‐sandwich complexes onto peptides in the presence of multiple coordinative motifs. Amenable to solid support, a range of N ‐terminus and/or lysine conjugated metal‐peptide conjugates were obtained in high purity after cleavage from the resin. The metalated peptides were evaluated for their anticancer properties against human cancer cell lines. While no cytotoxic activity was observed, this platform has the potential to i) provide a pathway to site‐selective peptide labelling, ii) be explored as a biorthogonal handle and/or iii) generate a new strategy for ligand design in transition metal catalysts.
Publisher: American Chemical Society (ACS)
Date: 21-08-2014
DOI: 10.1021/CR500200X
Publisher: Wiley
Date: 11-05-2023
Publisher: Wiley
Date: 11-05-2023
Abstract: Invited for the cover of this issue are Dan Furkert, Joe Bell‐Tyrer and co‐workers at the University of Auckland and Victoria University of Wellington. The image depicts a tandem cycloaddition–rearrangement process delivering a erse range of molecular frameworks from simple precursors. Read the full text of the article at 10.1002/chem.202300261 .
Publisher: Springer Science and Business Media LLC
Date: 30-11-2011
Publisher: Cambridge University Press (CUP)
Date: 15-09-2010
DOI: 10.1017/S0954102010000635
Abstract: Antarctic fishes survive freezing through the secretion of antifreeze glycoproteins (AFGPs), which bind to ice crystals to inhibit their growth. This mode of action implies that ice crystals must be present internally for AFGPs to function. The entry and internal accumulation of ice is likely to be lethal, however, so how do fishes survive in its presence? We propose a novel function for the interaction between internal ice and AFGPs, namely the promotion of ice uptake by splenic phagocytes. We show here that i) external mucus of Antarctic notothenioids contains AFGPs and thus has a potential protective role against ice entry, ii) AFGPs are distributed widely through the extracellular space ensuring that they are likely to come into immediate contact with ice that penetrates their protective barriers, and iii) using AFGP-coated nanoparticles as a proxy for AFGP adsorbed onto ice, we suggest that internal ice crystals are removed from the circulation through phagocytosis, primarily in the spleen. We argue that intracellular sequestration in the spleen minimizes the risks associated with circulating ice and enables the fish to store the ice until it can be dealt with at a later date, possibly by melting during a seasonal warming event.
Publisher: Royal Society of Chemistry (RSC)
Date: 2007
DOI: 10.1039/B709932K
Abstract: The synthesis of the spiroacetal-containing anti-Helicobacter pylori agents (3S,2''S,5''S,7''S)- (ent-CJ-12,954) and (3S,2''S,5''R,7''S)- (ent-CJ-13,014) has been carried out based on the convergent union of a 1:1 mixture of heterocycle-activated spiroacetal sulfones and with (3S)-phthalide aldehyde . The synthesis of the (3R)-diastereomers (3R,2''S,5''S,7''S)- and (3R,2''S,5''R,7''S)- was also undertaken in a similar manner by union of (3R)-phthalide aldehyde with a 1:1 mixture of spiroacetal sulfones and . Comparison of the (1)H and (13)C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2''S,5''S,7''S)- and (3S,2''S,5''R,7''S)- and the (3R)-diastereomers (3R,2''S,5''S,7''S)- and (3R,2''S,5''R,7''S)-, with the naturally occurring compounds, established that the synthetic isomers and were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014. The (2S,8S)-stereochemistry in protected dihydroxyketone , the precursor to the mixture of spiroacetal sulfones and was established via union of readily available (S)-acetylene with aldehyde in which the (4S)-stereochemistry was established via asymmetric allylation. Deprotection and cyclization of protected dihydroxyketone afforded an inseparable 1:1 mixture of spiroacetal alcohols and that were converted into a 1:1 inseparable mixture of spiroacetal sulfones and . Phthalide-aldehyde was prepared via intramolecular acylation of bromocarbamate in which the (3S)-stereochemistry was established via asymmetric CBS reduction of ketone .
Publisher: Elsevier BV
Date: 06-1997
Publisher: Wiley
Date: 25-11-2014
Abstract: The 2014 report from the World Health Organization (WHO) on antimicrobial resistance revealed an alarming rise in antibiotic resistance all around the world. Unlike classical antibiotics, with the exception of a few species, no acquired resistance towards antimicrobial peptides (AMPs) has been reported. Therefore, AMPs represent leads for the development of novel antibiotics. Caenopore-5 is constitutively expressed in the intestine of the nematode Caenorhabditis elegans and is a pore-forming AMP. The protein (82 amino acids) was successfully synthesised by using Boc solid-phase peptide synthesis and native chemical ligation. No γ-linked by-product was observed despite the use of a C-terminal Glu-thioester. The folding of the synthetic protein was confirmed by (1) H NMR spectroscopy and circular dichroism and compared with data recorded for recombinant caenopore-5. The permeabilisation activities of the protein and of shortened analogues were evaluated.
Publisher: Georg Thieme Verlag KG
Date: 10-2008
Publisher: CSIRO Publishing
Date: 2004
DOI: 10.1071/CH04021
Abstract: The first synthesis of a nucleoside analogue 1 is reported wherein the nucleobase 5-fluorocytosine is attached to a 1,6-dioxaspiro[5.5]undecane spiroacetal ring system. The spiroacetal system acts as a substitute for the sugar unit of natural nucleosides and provides a conformationally restricted framework upon which to append nucleobases in a well defined geometry. Trimethylsilyl triflate promoted Vorbrüggen-type coupling of bis(trimethylsilyl)-5-fluorocytosine 3 with spiroacetal acetate 2 provided spiroacetal nucleoside 1 in which the nucleobase occupied an equatorial position together with the ring opened (Z)-alkene 10. Spiroacetal acetate 2 serves as the spiroacetal donor and was prepared from the readily available starting materials δ-valerolactone and but-3-yn-1-ol 4.
Publisher: Wiley
Date: 18-10-2018
Abstract: The development of synthetic methods to prepare conformationally constrained peptides and peptide-polyketide hybrids remain an important chemical challenge. It is known that structural rigidity correlates with the specificity, bioactivity, and stability of these peptide systems, thus rigid systems are particularly attractive leads for development of potent biopharmaceuticals. Herein we provide an overview of recent developments in the syntheses of naturally derived constrained peptides and peptide-polyketide hybrids, with a particular emphasis on those systems containing an ene-like bond.
Publisher: American Chemical Society (ACS)
Date: 27-10-2017
DOI: 10.1021/ACSCHEMBIO.7B00845
Abstract: The development of a universal vaccine for influenza A virus (IAV) that does not require seasonal modification is a long-standing health goal, particularly in the context of the increasing threat of new global pandemics. Vaccines that specifically induce T cell responses are of considerable interest because they can target viral proteins that are more likely to be shared between different virus strains and subtypes and hence provide effective cross-reactive IAV immunity. From a practical perspective, such vaccines should induce T cell responses with long-lasting memory, while also being simple to manufacture and cost-effective. Here we describe the synthesis and evaluation of a vaccine platform based on solid phase peptide synthesis and bio-orthogonal conjugation methodologies. The chemical approach involves covalently attaching synthetic long peptides from a virus-associated protein to a powerful adjuvant molecule, α-galactosylceramide (α-GalCer). Strain-promoted azide-alkyne cycloaddition is used as a simple and efficient method for conjugation, and pseudoproline methodology is used to increase the efficiency of the peptide synthesis. α-GalCer is a glycolipid that stimulates NKT cells, a population of lymphoid-resident immune cells that can provide potent stimulatory signals to antigen-presenting cells engaged in driving proliferation and differentiation of peptide-specific T cells. When used in mice, the vaccine induced T cell responses that provided effective prophylactic protection against IAV infection, with the speed of viral clearance greater than that seen from previous viral exposure. These findings are significant because the vaccines are highly defined, quick to synthesize, and easily characterized and are therefore appropriate for large scale affordable manufacture.
Publisher: Georg Thieme Verlag KG
Date: 05-2007
Publisher: Elsevier BV
Date: 06-2015
Publisher: Elsevier BV
Date: 07-2002
Publisher: Wiley
Date: 06-06-2012
DOI: 10.1111/J.1742-4658.2012.08630.X
Abstract: Adiponectin is a collagenous adipokine with direct anti-diabetic and anti-atherogenic properties. It can assume an ensemble of oligomeric states, e.g. trimers, hexamers and octadecamers, each being involved in distinct signaling pathways relevant to adiponectin's erse biological function in metabolism, immunity, inflammation and cellular homeostasis. Assembly of the active variants principally the octadecameric high molecular weight form is achieved via the tightly controlled oxidation of cysteine 39 located in the adiponectin hyper-variable domain (AHD, residues 18-44) between the signal sequence and the collagen-like domain. We show that mutation of a highly conserved tryptophan (W42A) in the AHD profoundly affects assembly by trapping full-length adiponectin in the oxidized trimeric or hexameric states with a concomitant major reduction in the high molecular weight form. Our biophysical measurements on synthesized analogues of the AHD suggests that the aberrant oligomer distribution can be explained based on the fact that the proximity of W42 to C39 causes a reduction in the rate of C39 oxidation, an effect that to our knowledge has not been documented before. At the biological level, the perturbed oligomer distribution of full-length mutant adiponectin leads to a major reduction in the AMP-activated protein kinase activation in endothelial cells and liver tissues.
Publisher: American Chemical Society (ACS)
Date: 18-02-2015
DOI: 10.1021/JO502897U
Abstract: A convergent synthetic route to the sesterterpenoid framework of the bioactive phorbaketal and alotaketal natural product families has been established. The synthetic approach hinges on a Hosomi-Sakurai coupling of complex acetal and allylsilane coupling partners, followed by DDQ-promoted oxidative cyclization of highly unsaturated advanced intermediates. This robust synthetic approach enables further investigations into the members of these natural product families and readily provides access to analogues for biological testing.
Publisher: Elsevier BV
Date: 02-2010
Publisher: Bentham Science Publishers Ltd.
Date: 06-2006
DOI: 10.2174/157488906777452758
Abstract: The brain continues to remain an area where little corrective surgery can be performed. Recently, the ability to reverse some brain damage and perhaps prevent further damage has moved closer to hospitals and clinics. Several agents demonstrating neuroprotective properties and even neural regeneration have been developed to the extent that they have been granted patent protection, one of the first steps in commercial development. The concept of neuroprotection is the administration of an agent that can reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration due to oxidative stress whilst other agents specifically protect against neural stroke damage. In the early years of neuroprotective research, most compounds were not designed as such but were found to possess neuroprotective activity in later studies. However, the original structures have since become the leads for purely synthetic derivatives. Most of the agents are or were designed from biologically active natural products, either plant extracts or endogenous peptides roteins and even sequences of RNA. This review will present the most recently patented neuroprotective agents.
Publisher: Georg Thieme Verlag KG
Date: 03-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0SC00194E
Publisher: The Endocrine Society
Date: 03-2015
DOI: 10.1210/EN.2014-1593
Abstract: The search for an islet β-cell growth factor has been a key objective in recent diabetes research, because the ability to regenerate and/or protect the functioning β-cell population in patients could result in a great advancement for diabetes treatment. IGF-I and IGF-II are known to play crucial roles in fetal growth and prenatal development, and there is growing evidence that IGF-II increases β-cell proliferation and survival in vitro and in vivo. A search for the source of IGF-II–like immunoreactivity in isolated β-cell secretory granules from the murine cell line βTC6-F7 revealed a novel 2-chain IGF-II–derived peptide, which we named vesiculin and which has been shown to be a full insulin agonist. Here, we present a liquid chromatography–tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related IGF-II and vesiculin molecules. We have used this method to measure these 2 peptides in conditioned media from 2 β-cell lines, produced under increasing glucose concentrations. This technique detected both IGF-II and vesiculin in media conditioned by MIN6 and βTC6-F7 cells at levels in the range of 0 to 6 μM (total insulin, 80–450 μM) and revealed a glucose-stimulated increase in insulin, IGF-II, and vesiculin. IGF-II was detected in adult human and neonatal mouse serum in high levels, but vesiculin was not present. The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance.
Publisher: American Chemical Society (ACS)
Date: 08-11-2013
DOI: 10.1021/JO402220S
Abstract: An efficient, robust, and scalable synthesis of an azido precursor to the modified amino acid (2S,5R)-5-hydroxylysine was developed on the basis of the use of a highly stereoselective organocatalytic α-chlorination-reduction protocol. The final Fmoc-protected (2S,5R)-6-azido-5-hydroxylysine derivative can be used in solid-phase peptide synthesis, providing access to proteins that contain large quantities of post-translationally modified lysine (e.g., collagens).
Publisher: Wiley
Date: 29-05-2017
Publisher: Elsevier BV
Date: 04-1998
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B612757F
Abstract: The first synthesis of the spiroacetal-containing anti-Helicobacter pylori agents ent-CJ-12,954 and ent-CJ-13,014 is reported based on the union of a heterocycle-activated spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragment comparison of the 1H and 13C NMR data, optical rotations and HPLC retention times of the synthetic compounds (3S,2"S,5"S,7"S)-(1a) and (3S,2"S,5"R,7"S)-(2a) and the (3R)-diastereomers (3R,2"S,5"S,7"S)-(1b) and (3R,2"S,5"R,7"S)- (2b) with the naturally occurring compounds established that the synthetic isomers (1a) and (2a) were in fact enantiomeric to the natural products CJ-12,954 and CJ-13,014.
Publisher: Elsevier BV
Date: 04-1994
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.BMC.2005.04.054
Abstract: Bicyclic analogues of methyllycaconitine (MLA), such as 12, have been synthesised that incorporate the C1-OMe substituent present in the natural product. Electrophysiology experiments using Xenopus oocytes expressing nicotinic acetylcholine receptors (nAChRs) were conducted on these analogues and a related tricyclic analogue 2. The most potent compound, 2, was an antagonist at all receptors studied but displayed different antagonist effects at each receptor subtype. This study more clearly defines the biological effects of MLA analogues at nAChRs and demonstrates that these analogues are not selective ligands for the alpha7 nAChR subtype.
Publisher: Elsevier BV
Date: 1986
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2OB06802H
Abstract: The enantioselective synthesis of novel C-linked spiroacetal-triazoles 10 is reported. The key step involves reaction of acetylenic spiroacetal 11 with several azides by the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC). The biologically privileged spiroacetal scaffold 11 was prepared from silyl-protected Weinreb amide 19 using several reliable Grignard additions and a highly diastereoselective enzymatic kinetic resolution.
Publisher: Georg Thieme Verlag KG
Date: 30-09-2010
Publisher: Georg Thieme Verlag KG
Date: 04-04-2011
Publisher: Wiley
Date: 05-12-2016
Publisher: Wiley
Date: 10-07-2019
Abstract: Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity.
Publisher: American Chemical Society (ACS)
Date: 08-05-2009
DOI: 10.1021/OL9005536
Abstract: Microwave-enhanced click glycoconjugation of a propargylated alpha-GalNAc sugar moiety with an azido-functionalized amino acid or multiazido-functionalized peptides using a catalytic quantity of Cu(I) enabled a high-yielding and rapid synthesis of a "Tn-antigen mimic" and click analogues of antifreeze glycopeptides, thus demonstrating a valuable synthetic platform for the synthesis of biologically relevant neoglycopeptides.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.BBABIO.2007.04.002
Abstract: It was recently demonstrated that the rat-selective toxicant norbormide also induces rat-selective opening of the permeability transition pore (PTP) in isolated mitochondria. Norbormide is a mixture of endo and exo stereoisomers however, only the endo forms are lethal to rats. In the present study we tested both endo and exo isomers as well as neutral and cationic derivatives of norbormide to: (i) verify if the PTP-regulatory activity by norbormide is stereospecific (ii) define the structural features of norbormide responsible for PTP-activation, (iii) elucidate the basis for the drug species-specificity. Our results show that: (i) norbormide isomers affect PTP in a rat-selective fashion however, no relevant differences between lethal and non-lethal forms are observed suggesting that drug regulation of PTP-activity and lethality in rats are unrelated phenomena (ii) a (phenylvinyl)pyridine moiety represents the key element conferring the PTP-activating effect (iii) cationic derivatives of rat-active compounds accumulate in the matrix via the membrane potential and activate the PTP also in mouse and guinea pig mitochondria. These findings suggest that the norbormide-sensitive PTP-target is present in all species examined, and is presumably located on the matrix side. The species-selectivity may depend on the unique properties of a transport system allowing drug internalisation in rat mitochondria.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMECH.2017.05.008
Abstract: The 20-residue linear peptide A20FMDV2 has been shown to exhibit high selectivity and affinity for the tumour-related αvβ6 integrin and has potential as a vector for therapeutic drugs. However, it exhibits poor half-life in plasma in part due to its high susceptibility to serum proteases. In this study fourteen A20FMDV2 analogues incorporating non-proteinogenic substitutes of the native Lys16 and Leu13 residues and six A20FMDV2 analogues containing modified N- and C-termini were synthesised to increase the half-life and activity of A20FMDV2. The analogues incorporating modified terminal motifs of A20FMDV2 were found to strongly bind to the αvβ6 integrin and were subsequently functionalized with the diethylenetriaminepentaacetic acid chelating agent to facilitate coupling with radioactive indium-111 for human plasma stability and in vivo biodistribution studies. A20FMDV2 peptide variants incorporating an N-terminal d-Asn and C-terminal d-Thr exhibited improved relative activity in vitro and were less susceptible to plasma degradation.
Publisher: International Union of Crystallography (IUCr)
Date: 13-09-2008
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0NP00039F
Abstract: This review provides a comprehensive summary of the literature relating to ent -atisane diterpenoids spanning the 50 years following their initial discovery.
Publisher: Georg Thieme Verlag KG
Date: 22-06-2005
Publisher: Georg Thieme Verlag KG
Date: 09-2007
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.BMC.2013.06.071
Abstract: Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB-derived prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality alatability in vivo) is described. Prodrug 2 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats. Moreover, prodrug 25 was found to be largely accepted by rats in a choice trial, resulting in high mortality.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3OB40322J
Abstract: Diabetes mellitus, characterised by hyperglycemia and altered β-cell function, is an increasingly common disorder affecting millions of in iduals world-wide. While therapeutic regimens exist to manage the condition, diabetic in iduals remain prone to complications that are detrimental to both their length and quality of life. An improved understanding of the disease which may then enable development of new treatments is therefore a desirable goal. Vesiculin, a novel IGF-II-like protein was recently isolated from the secretory granules of murine β-cells, and preliminary studies indicate it is capable of signalling via the insulin receptor (IR)/insulin-like growth factor receptor 1(IGF1R) family giving it the potential to elicit both metabolic and mitogenic responses in the beta-cell. In order to facilitate further studies on this new member of the insulin-family of hormones, we undertook a chemical synthesis of the protein using regioselective disulfide bond formation.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6OB01455K
Abstract: Replacement of serine at position 3 of preptin (1-16) with alanine increased the proliferation and matrix mineralisation of foetal cultures of primary rat osteoblasts in vitro .
Publisher: Georg Thieme Verlag KG
Date: 09-2007
Publisher: Elsevier BV
Date: 10-2017
Publisher: Elsevier BV
Date: 06-1999
Publisher: Wiley
Date: 12-05-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B605293B
Abstract: The syntheses of seven macrocyclic analogues of the neuroprotective tripeptide glycyl-L-prolyl-L-glutamic acid (GPE) are described. Macrocycles 6 and 7 mimic the cis conformer of GPE whereas macrocycles 2-5, 8, and 9 mimic the trans conformer of GPE. The macrocyclic peptides of well-defined geometry were prepared via Grubbs ring closing metathesis of an appropriate diene precursor. In turn each of the diene precursors were prepared from the readily available allyl-substituted amino acid building blocks 12, 13, 14, 27, 36 and 51.
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B800164M
Abstract: In order to survive extremes of pH, temperature, salinity and pressure, organisms have been found to develop unique defences against their environment, leading to the biosynthesis of novel molecules ranging from simple osmolytes and lipids to complex secondary metabolites. This review highlights novel molecules isolated from microorganisms that either tolerate or favour extreme growth conditions.
Publisher: Elsevier BV
Date: 05-1998
Publisher: International Union of Crystallography (IUCr)
Date: 22-02-2006
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2MD00314G
Publisher: Wiley
Date: 29-10-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B708811F
Abstract: A review of the isolation, biological activity and synthesis of pyranonaphthoquinones and closely related compounds is provided.
Publisher: Elsevier BV
Date: 1992
Publisher: Springer Science and Business Media LLC
Date: 29-03-1996
Publisher: American Chemical Society (ACS)
Date: 13-07-2018
DOI: 10.1021/ACS.BIOCHEM.8B00502
Abstract: Calcitonin gene-related peptide (CGRP) binds to the complex of the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). How CGRP interacts with the transmembrane domain (including the extracellular loops) of this family B receptor remains unclear. In this study, a photoaffinity cross-linker, p-azido l-phenylalanine (azF), was incorporated into CLR, chiefly in the second extracellular loop (ECL2) using genetic code expansion and unnatural amino acid mutagenesis. The method was optimized to ensure efficient photolysis of azF residues near the transmembrane bundle of the receptor. A CGRP analogue modified with fluorescein at position 15 was used for detection of ultraviolet-induced cross-linking. The methodology was verified by confirming the known contacts of CGRP to the extracellular domain of CLR. Within ECL2, the chief contacts were I284 on the loop itself and L291, at the top of the fifth transmembrane helix (TM5). Minor contacts were noted along the lip of ECL2 between S286 and L290 and also with M223 in TM3 and F349 in TM6. Full length molecular models of the bound receptor complex suggest that CGRP sits at the top of the TM bundle, with Thr
Publisher: Wiley
Date: 2007
DOI: 10.1002/JLCR.1262
Publisher: Elsevier BV
Date: 11-2011
Publisher: Elsevier BV
Date: 04-2001
Publisher: MDPI AG
Date: 27-09-2021
DOI: 10.3390/MOLECULES26195847
Abstract: The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market ‘boom’, garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma. Herein we review the enthusiasm for ADCs by focusing on the features of those approved by the FDA, and offer some thoughts as to where the field is headed.
Publisher: American Chemical Society (ACS)
Date: 07-2005
DOI: 10.1021/OL051260U
Abstract: An enantioselective synthesis of the bis-spiroacetal fragment of spirolides B and D is reported. The carbon framework was constructed via Barbier reaction of dihydropyran 3 with aldehyde 4, followed by a double oxidative radical cyclization to construct the bis-spiroacetal. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor. The initial unsaturated bis-spiroacetals 2a-d underwent equilibration during epoxidation to trans-epoxide 14 that was converted to a tertiary alcohol. [reaction: see text]
Publisher: Wiley
Date: 11-08-2015
Publisher: American Chemical Society (ACS)
Date: 14-09-2002
DOI: 10.1021/OL026605C
Abstract: [reaction: see text] A synthetic approach to the novel bis-spiroacetal moiety of spirolides B and D is reported. The strategy hinges upon successive formation of the spirocenters at C15 and C18 by radical oxidative cyclization, followed by base-induced rearrangement of a C19-20 alpha-epoxide to introduce the C19 hydroxyl group.
Publisher: Wiley
Date: 30-09-2019
Publisher: MDPI AG
Date: 09-11-2022
Abstract: Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy in iduals and migraine-like attacks in patients however, it is not clear whether targeting this system could be therapeutically efficacious. To effectively target the PACAP system, an understanding of PACAP receptor distribution is required. Therefore, this study aimed to characterize commercially available antibodies and use these to detect PACAP-responsive receptors in the TG. Antibodies were initially validated in receptor transfected cell models and then used to explore receptor expression in rat and human TG. Antibodies were identified that could detect PACAP-responsive receptors, including the first antibody to differentiate between the PAC1n and PAC1s receptor splice variants. PAC1, VPAC1, and VPAC2 receptor-like immunoreactivity were observed in subpopulations of both neuronal and glial-like cells in the TG. In this study, PAC1, VPAC1, and VPAC2 receptors were detected in the TG, suggesting they are all potential targets to treat migraine. These antibodies may be useful tools to help elucidate PACAP-responsive receptor expression in tissues. However, most antibodies exhibited limitations, requiring the use of multiple methodologies and the careful inclusion of controls.
Publisher: Elsevier BV
Date: 02-2013
Publisher: Elsevier BV
Date: 1995
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3OB41951G
Abstract: The Human Rhinovirus (HRV) is the major aetiological agent for the common cold, for which only symptomatic treatment is available. HRV maturation and replication is entirely dependent on the activity of a virally encoded 3C protease that represents an attractive target for the development of therapeutics to treat the common cold. Herein we report the synthesis and biological evaluation of the 2-methylene analogue of the HRV 3C protease inhibitor (-)-thysanone (1) namely 2-carbathysanone (2), in an attempt to decipher the structural features in the natural product that are responsible for the 3C protease activity. 2-Carbathysanone (2) (and related analogues (±)-cis-23, (±)-cis-30, (±)-31) did not inhibit HRV 3C protease, indicating that the lactol functionality present in (-)-thysanone (1) is a critical structural feature required for inhibition.
Publisher: Elsevier BV
Date: 03-1998
Publisher: Elsevier BV
Date: 05-2008
Publisher: Wiley
Date: 19-10-2021
Abstract: TLR2 agonists are at the forefront of vaccine research for a plethora of diseases, in particular they offer a promising tool for the treatment of cancer. A detailed knowledge of their structure–activity relationship informs the methodical design of vaccine constructs that include TLR2 agonists. Herein we report the design, synthesis, and biological evaluation of analogues of the TLR2 agonist Pam 2 Cys to further probe structure–activity relationships. These analogues replace one or other of the two ester groups with ether functionalities to elucidate the role of the carbonyls on TLR2 activity. Through this we demonstrate that the C3 ester carbonyl is dispensable, but the C2 carbonyl is essential for activity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0NP00021C
Abstract: Extremophiles continue to capture attention. This update highlights the structures of novel molecules isolated from extremophilic and extreme-tolerant microorganisms in the last decade.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1OB05777D
Abstract: Dehydrotryptophan and its derivatives are non-proteinogenic amino acids commonly found in peptide-based natural products produced by microorganisms, marine organisms and plants. These non-proteinogenic amino acids are found in secondary metabolites and are formed by post translational modification processes. Although comprehensive reviews on the synthesis of dehydroamino acids are available, this perspective focuses solely on methods to synthesise the dehydrotryptophan-containing segment of naturally occurring peptides, amino acids and their derivatives.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3OB00360D
Abstract: The variables effecting successful depsipeptide (ester) bond formation, on-resin, are prioritised to provide a useful troubleshooting guide for depsipeptide synthesis.
Publisher: Elsevier BV
Date: 03-2000
Publisher: Georg Thieme Verlag KG
Date: 05-10-2020
DOI: 10.1055/A-1282-6870
Abstract: The first total synthesis of the allene-containing cyclic tetrapeptide pseudoxylallemycin C is reported. The Tyr(t-Bu)-protected linear peptide was prepared on-resin and cyclized in solution phase to yield the protected cyclic precursor. Upon deprotection of Tyr(t-Bu), the desired phenolic cyclic tetrapeptide was separated by RP-HPLC from its epimer that also formed during the macrocyclisation step. Subsequent alkylation with 4-bromobuta-1,2-diene yielded pseudoxylallemycin C.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2021
Publisher: International Union of Crystallography (IUCr)
Date: 14-03-2008
Publisher: Elsevier BV
Date: 1995
Publisher: Wiley
Date: 17-02-2020
Abstract: Lipidation is a key modification affecting the physiochemical properties of peptides and widely used in the design of drug candidates. Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) enables rapid synthesis of a library of S‐lipidated peptides via a thiol‐ene reaction between a free sulfhydryl group on cysteine‐containing peptide and a vinyl ester bearing a lipid. Optimization of the CLipPA procedure was performed by replacing the malodorous tert ‐butylthiol and modifying the work‐up procedure to facilitate the analysis and isolation of lipopeptides.
Publisher: American Chemical Society (ACS)
Date: 02-08-2019
Publisher: Wiley
Date: 05-12-2008
Publisher: Walter de Gruyter GmbH
Date: 31-10-2011
Abstract: Studies toward the synthesis of three biologically active [5,6]-benzannulated spiroketal natural products are described. The first total synthesis of paecilospirone is reported, employing a late-stage, pH-neutral spiroketalization. A formal synthesis of γ-rubromycin is described, where the spiroketal moiety is formed by delicate manipulation of the electronic properties of the spirocyclization precursor. Finally, model work toward the total synthesis of berkelic acid is summarized, introducing a novel Horner–Wadsworth–Emmons/oxa-Michael (HWE/oxa-M) cascade to access the spiroketal precursor.
Publisher: Elsevier BV
Date: 12-1994
Publisher: American Chemical Society (ACS)
Date: 15-09-2023
Publisher: Hindawi Limited
Date: 03-02-2020
DOI: 10.1002/ER.5159
Publisher: American Chemical Society (ACS)
Date: 17-01-2013
DOI: 10.1021/OL303482K
Abstract: The first total synthesis of the monoamine oxidase inhibitors chaetoquadrins A-C has been accomplished. Key steps in the synthesis include an aromatic Claisen rearrangement, asymmetric boron aldol reaction and acid-mediated spiroketalization. Comparison of spectral data for the synthetic spiroketals confirmed the proposed structure for these natural products.
Publisher: Elsevier BV
Date: 06-2004
Publisher: American Chemical Society (ACS)
Date: 28-01-2020
DOI: 10.1021/ACS.ORGLETT.9B04567
Abstract: 2-Bromo-1,3-butadienes are demonstrated to be effective substrates for tandem Diels-Alder/transition metal cross-coupling reaction sequences. Intermolecular cycloaddition of a 2-bromo-1,3-diene with activated dienophiles proceeded under Lewis acid catalysis in generally high yields with good to excellent
Publisher: American Chemical Society (ACS)
Date: 19-06-2018
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.BMC.2004.10.004
Abstract: The synthesis of 10 G*PE analogues, wherein the glycine residue has been modified, is described by coupling readily accessible dibenzyl-L-prolyl-L-glutamate 2 with various analogues of glycine. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glycine residue on the observed neuroprotective properties of the endogenous tripeptide GPE.
Publisher: Elsevier BV
Date: 1985
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.BMC.2004.10.005
Abstract: The synthesis of nine GPE* analogues, wherein the alpha-carboxylic acid group of glutamic acid has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline 2 with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.BMC.2004.10.006
Abstract: The synthesis of eight GPE* analogues, wherein the gamma-carboxylic moiety of the glutamic residue has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.
Publisher: Wiley
Date: 23-07-2020
Publisher: Wiley
Date: 14-12-2020
Abstract: Callyspongiolide, a macrolide natural product with a conjugated diene‐ynic side chain, has garnered significant attention from the synthetic community since its isolation from a sea sponge in 2013. Herein, the approaches that have been applied to this bioactive natural product to date are reviewed. These synthetic endeavors have established the absolute stereochemistry of this molecule and allowed further investigation into its promising caspase‐independent bioactivity, while also contributing to the wider field of macrolide synthesis.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8NP00051D
Abstract: 2-Formylpyrroles constitute a large and growing family of bioactive Maillard reaction products found in food, traditional medicine and throughout nature.
Publisher: Elsevier BV
Date: 06-2009
Publisher: American Chemical Society (ACS)
Date: 02-08-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B611531B
Abstract: In this article we provide an overview of synthetic studies towards pectenotoxins (PTXs) that have been reported by several research groups. The difficulties encountered in the synthesis of these series of polyketides are highlighted by the fact that only one total synthesis of PTX4 and PTX8 has been completed to date. The strategies used in the critical bond forming steps and the introduction of key stereogenic centres are compared and contrasted.
Publisher: American Chemical Society (ACS)
Date: 11-11-2014
DOI: 10.1021/JO502238R
Abstract: Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported. The synthesis used key elements from the synthesis of palmyrolide A, including the RCM/olefin isomerization sequence. The synthetic work described herein serves to facilitate the assignment of stereochemistry of the natural product sanctolide A and demonstrates the utility of this approach for the synthesis of macrocyclic tertiary enamide natural products.
Publisher: Elsevier BV
Date: 08-2021
Publisher: American Chemical Society (ACS)
Date: 23-07-2014
DOI: 10.1021/JO501344C
Abstract: A full account of our efforts toward an asymmetric synthesis of crisamicin A are presented. The key steps include a Hauser-Kraus annulation of a cyanophthalide with a chiral enone-lactone, a stereoselective cyclization-reduction to install the pyran unit, and a Suzuki homocoupling to forge the key biaryl bond. This work has culminated in the asymmetric synthesis of a dimer bearing the complete carbon skeleton of the dimeric pyranonaphthoquinone natural product crisamicin A.
Publisher: International Union of Crystallography (IUCr)
Date: 28-02-2006
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB00072G
Abstract: The use of a bi-functional linker, containing an alkyne and an alkene, allows the protecting group free conjugation of reducing sugars to thiols via a double click process.
Publisher: Elsevier BV
Date: 04-2008
Publisher: Bentham Science Publishers Ltd.
Date: 06-2021
DOI: 10.2174/0929867327666201006153847
Abstract: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding which can help formulate novel combination therapeutic regimens and more accurate diagnosis avoiding unnecessary prostate biopsies. This accumulated knowledge also provides greater understanding into aggressive stages of the disease and tumour recurrence. Recently, much progress has been made on developing peptidomimetic-based inhibitors as promising candidates to effectively bind to the prostate-specific membrane antigen (PSMA) which is expressed by prostate cancer cells. In this review, recent advances covering small-molecule and peptide-based PSMA inhibitors will be extensively reviewed, providing a base for the rational design of future PSMA inhibitors. Herein, the literature on selected PSMA inhibitors that have been developed from 1996 to 2020 were reviewed, emphasizing recent synthetic advances and chemical strategies whilst highlighting therapeutic potential and drawbacks of each inhibitor. Synthesized inhibitors presented in this review demonstrate the clinical application of certain PSMA inhibitors, exhibited in vitro and in vivo. This review highlights the clinical potential of PSMA inhibitors, analyzing the advantages and setbacks of the chemical synthetic methodologies utilized, setting precedence for the discovery of novel PSMA inhibitors for future clinical applications.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0OB00203H
Abstract: Cyclic lipopeptides are often challenging synthetic targets. A synthetic approach is presented that employs cyclisation by intramolecular native chemical ligation (NCL) and a thiol–ene “CLipPA” reaction to afford S -lipidated analogues of iturin A.
Publisher: Georg Thieme Verlag KG
Date: 24-02-2009
Publisher: American Chemical Society (ACS)
Date: 10-11-2017
DOI: 10.1021/ACS.BIOMAC.7B01245
Abstract: Six guanidine functionalized aliphatic biodegradable polycarbonates with varying molecular weights and charge densities were synthesized via postsynthesis modification of alkyne containing polycarbonates using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry. The concept of passive diluting group was to modify the cationic charge density of the polycarbonate without changing its hydrophilicity. Within the molecular weight range from 8000 to 30000 g mol
Publisher: American Chemical Society (ACS)
Date: 27-04-2018
DOI: 10.1021/ACSCHEMBIO.8B00055
Abstract: Glycocin F, a bacteriocin produced by Lactobacillus plantarum KW30, is glycosylated with two N-acetyl-d-glucosamine sugars, and has been shown to exhibit a rapid and reversible bacteriostasis on susceptible cells. The roles of certain structural features of glycocin F have not been studied to date. We report here the synthesis of various glycocin F analogues through solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL), allowing us to probe the roles of different structural features of this peptide. Our results indicate that the bacteriostatic activity of glycocin F is controlled by the glycosylated interhelical loop, while the glycosylated flexible tail appears to be involved in localizing the peptide to its cellular target.
Publisher: American Chemical Society (ACS)
Date: 30-04-2003
DOI: 10.1021/OL034370E
Abstract: [reaction: see text] Several dienes embedded in di- and tripeptides which incorporate proline have been prepared and subjected to ring-closing metathesis. Bicyclic peptides of well-defined amide geometry and of varying ring sizes were prepared. Several limitations of the cyclization step were revealed.
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0CC00056F
Abstract: Use of a bis-dithiane deprotection-tandem bis-spiroacetalisation sequence was key to the successful synthesis of the [5,6,6]-bis-spiroacetal of the antimitotic agent spirastrellolide B, achieved in a highly convergent fashion involving successive dithiane alkylations.
Publisher: Georg Thieme Verlag KG
Date: 04-2008
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8SC03409E
Abstract: The batch-wise variability of commercial erythropoietin (EPO) preparations warrants development of more advanced synthetic methodologies. We have developed a erse chemical toolkit to prepare ‘click’ neoglycoprotein variants of EPO.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9OB00227H
Abstract: During total synthesis of pseudoxylallemycin A, an unstable intermediate was observed and appeared to be reactivated by coupling reagent by-products.
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B712926B
Abstract: Mannose-binding proteins on the surface of antigen-presenting cells (APCs) are capable of recognizing and internalizing foreign agents in the early stages of immune response. These receptors offer a potential target for synthetic vaccines, especially vaccines designed to stimulate T cells. We set out to synthesize a series of fluorescein-labelled O-mannosylated peptides using manual solid phase peptide synthesis (SPPS) on pre-loaded Wang resin, in order to test their ability to bind mannose receptors on human APCs in vitro. A flexible and reliable method for the synthesis of fluorescein-labelled O-mannosylated glycopeptides was desired in order to study their lectin-binding properties using flow cell cytometry. Two synthetic strategies were investigated: incorporation of a fluorescein label into the peptide chain via a lysine side chain epsilon-amino group at the final stage of standard Fmoc solid phase peptide synthesis or attachment of the fluorescein label to the N(alpha)-amino group of a lysine with further incorporation of a mannosylated peptide unit through the side chain N(epsilon)-amino group. The latter strategy proved more effective in that it facilitated SPPS by positioning the growing mannosylated peptide chain further removed from the fluorescein label.
Publisher: Elsevier BV
Date: 1987
Publisher: Elsevier BV
Date: 08-1991
Publisher: Elsevier BV
Date: 05-1997
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2OB02262A
Abstract: Cysteine-selective thia-Michael addition provides opportunities in chemistry, biology, and medicine.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH12393
Abstract: A series of pyranonaphthoquinone derivatives possessing structural features present in both natural products annulin B and exiguamine A have been shown to exhibit low micromolar inhibition of indoleamine 2,3-dioxygenase-1 (IDO-1). These inhibitors retain activity against the enzyme in a cellular context with an approximate one-log loss of dose potency against IDO-1 in cells. One particular analogue, triazole 8 shows good inhibition of IDO-1 along with little loss of cell viability at low drug concentrations. These results have extended the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature.
Publisher: MDPI AG
Date: 20-02-2023
DOI: 10.3390/MOLECULES28041993
Abstract: Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH2-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog Paa yunnanensis (PY) and reported to possess broad-spectrum antibacterial and antifungal properties, exhibiting low cytotoxic and low hemolytic activity. Herein, we detail the total synthesis of cathelicidin-PY using an entirely on-resin synthesis, including assembly of the linear sequence by rapid flow Fmoc-SPPS and iodine-mediated disulfide bridge formation. By optimising a synthetic strategy to prepare cathelicidin-PY, this strategy was subsequently adapted to prepare a bicyclic head-to-tail cyclised derivative of cathelicidin-PY. The structure-activity relationship (SAR) of cathelicidin-PY with respect to the N-terminally positioned disulfide was further probed by preparing an alanine-substituted linear analogue and a series of lactam-bridged peptidomimetics implementing side chain to side chain cyclisation. The analogues were investigated for antimicrobial activity, secondary structure by circular dichroism (CD), and stability in human serum. Surprisingly, the disulfide bridge emerged as non-essential to antimicrobial activity and secondary structure but was amenable to synthetic modification. Furthermore, the synthetic AMP and multiple analogues demonstrated selective activity towards Gram-negative pathogen E. coli in physiologically relevant concentrations of alent cations.
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2NJ01016J
Abstract: Intramolecular ring-closing metathesis on an N , N -diallyl Glu-urea-Gly substrate affords 7-membered cyclic ureas as inhibitors of prostrate specific membrane antigen (PMSA).
Publisher: International Union of Crystallography (IUCr)
Date: 24-09-2008
Publisher: Wiley
Date: 23-02-2018
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.JNS.2008.12.003
Abstract: The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.
Publisher: Wiley
Date: 07-09-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB00541E
Abstract: An interesting family of bioactive aminolipopeptides contain the unusual building block 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD).
Publisher: American Chemical Society (ACS)
Date: 20-10-2011
DOI: 10.1021/JO201729T
Abstract: The spirastrellolides are a family of potent antimitotic agents isolated from the marine sponge Spirastrella coccinea . Synthetic studies toward the DEF bis-spiroacetal core of spirastrellolide B are reported. A modular approach was pursued by the use of two dithiane disconnections to enable a highly convergent synthesis. The ease of lithiation and nucleophilicity of these 2-substituted-1,3-dithianes were investigated during the course of the synthesis, and the alkylations were found to proceed most efficiently at elevated temperatures. Formation of the [5,6,6]-bis-spiroacetal ring system was achieved via a double dithiane deprotection/spiroacetalization strategy.
Publisher: American Chemical Society (ACS)
Date: 19-08-2013
DOI: 10.1021/OL402191T
Abstract: The first total synthesis of the benzannulated spiroketal virgatolide A is presented. Key features include sp(3)-sp(2) Suzuki coupling of an enantiomerically enriched β-trifluoroboratoamide and an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction followed by global deprotection/cyclization with regioselectivity governed by internal hydrogen bonding.
Publisher: American Chemical Society (ACS)
Date: 16-06-2017
DOI: 10.1021/ACS.ORGLETT.7B01371
Abstract: The total synthesis of both enantiomers of pestalospirane B, 2, has been achieved using a bioinspired tandem dimerization-spiroketalization reaction. Electronic circular dichroism (ECD) and X-ray analysis were used to revise the absolute stereochemistry of the natural product pestalospirane B from 3S, 3'S, 12R, 12'R to its enantiomer 3R, 3'R, 12S, 12'S.
Publisher: Royal Society of Chemistry (RSC)
Date: 1999
DOI: 10.1039/A804287J
Publisher: Elsevier BV
Date: 06-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B905077A
Abstract: Studies towards the biomimetic synthesis of cardinalin 3 are described. Despite the successful enantioselective synthesis of the monomeric pyranonaphthoquinone ventiloquinone L, it subsequently failed to undergo a proposed biomimetic homodimerisation to cardinalin 3 using a range of oxidants. However, treatment of a related naphthopyran with cerium ammonium nitrate (CAN) facilitated a tandem biaryl bond formation-oxidative demethylation sequence furnishing a dimeric pyranonaphthoquinone that had exclusively dimerised at C6. The nature of this unusual sequence is discussed and the product subsequently converted to the C6 regioisomer of cardinalin 3.
Publisher: American Chemical Society (ACS)
Date: 23-11-2010
DOI: 10.1021/JO102038Q
Abstract: An efficient stereoselective synthesis of fully protected (2S,4R)-4-methylpipecolic acid has been developed. The synthesis was achieved by initial asymmetric α-alkylation of glycine with a chiral iodide, affording the linear precursor as a single stereoisomer. Subsequent aldehyde formation using OsO(4)/NaIO(4) followed by immediate intramolecular cyclization afforded an enamine that was then subjected to hydrogenation to give the final compound in 23% yield over 10 steps.
Publisher: CSIRO Publishing
Date: 2003
DOI: 10.1071/CH02236
Abstract: In connection with studies directed towards the synthesis of the pyranonaphthoquinone antibiotic medermycin, C-aryl glycosides were prepared by C-glycosylation of naphthols with glycosyl donors. Boron trifluoride diethyl etherate proved to be a suitable Lewis acid to promote the C-glycosylation, and use of the azido glycosyl donor proved more successful than using the dimethylamino glycosyl donor. 5-Hydroxy-1,4-dimethoxynaphthalene underwent facile C-glycosylation with two particular glycosyl donors, whereas 3-bromo-5-hydroxy-1,4-dimethoxynaphthalene was not an effective coupling partner with the same glycosyl donors. These studies indicate that subtle steric and electronic effects need to be considered in order to fine-tune C-glycosylations when using highly functionalized glycosyl donors.
Publisher: Elsevier BV
Date: 2015
Publisher: Georg Thieme Verlag KG
Date: 21-08-2009
Publisher: Elsevier BV
Date: 07-2004
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2OB26082D
Abstract: The Kulinkovich cyclopropanation reaction provides a flexible and convenient method for the synthesis of cyclopropanols. Together with the erse chemistry of the cyclopropanol unit, it offers access to a wide range of functionalised unsaturated and saturated compounds. The successful use in the synthesis of natural compounds is outlined in this perspective.
Publisher: American Chemical Society (ACS)
Date: 09-2021
Publisher: Elsevier BV
Date: 03-2006
Publisher: American Chemical Society (ACS)
Date: 29-06-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B808454H
Abstract: The elaboration of a 6,6-spiroacetal scaffold to incorporate a triazole unit as a peptide bond surrogate at the anomeric position is described. The novel spiroacetal-triazole hybrid structures were generated via cycloaddition of a spiroacetal azide to a series of alkynes. The spiroacetal framework was constructed via Barbier reaction of bromide 10 with Weinreb amide 11, followed by acid-catalysed deprotection and cyclisation to afford the 6,6-spiroacetal ring system. The resultant ethoxy-spiroacetal 8 was converted to spiroacetal azide 5, which was then elaborated into a series of spiroacetal-triazole derivatives 7.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC02170H
Abstract: Tikitericin, a novel lanthipeptide was isolated and characterised together with its first total synthesis.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0OB01997F
Abstract: Highly potent anti-HBV lipopeptides were prepared by S -lipidation using the “Cysteine Lipidation on a Peptide or Amino Acid” (CLipPA) thiol–ene reaction. Interestingly, target binding efficacy correlated poorly with inhibitory potency.
Publisher: Springer Science and Business Media LLC
Date: 05-1990
DOI: 10.1007/BF01014100
Publisher: Wiley
Date: 12-05-2016
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.BMCL.2018.05.048
Abstract: Energy generation is a promising area of drug discovery for both bacterial pathogens and parasites. Type II NADH dehydrogenase (NDH-2), a vital respiratory membrane protein, has attracted attention as a target for the development of new antitubercular and antimalarial agents. To date, however, no potent, specific inhibitors have been identified. Here, we performed a site-directed screening technique, tethering-fragment based drug discovery, against wild-type and mutant forms of NDH-2 containing engineered active-site cysteines. Inhibitory fragments displayed IC
Publisher: Wiley
Date: 23-05-2017
Publisher: American Chemical Society (ACS)
Date: 20-07-2022
DOI: 10.1021/JACS.2C04146
Abstract: Herein we report the first ex les of thiol-selective heterobifunctional electrophiles,
Publisher: MDPI AG
Date: 14-01-2023
DOI: 10.3390/PHARMACEUTICS15010287
Abstract: Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel.
Publisher: Georg Thieme Verlag KG
Date: 14-05-2009
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8OB02982B
Abstract: Through chemical synthesis we have designed out the toxicity associated with the powerful vaccine adjuvant α-GalCer.
Publisher: Georg Thieme Verlag KG
Date: 13-05-2011
Publisher: Elsevier BV
Date: 06-2020
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/CH12168
Abstract: We report the dramatic effect of rationally-designed phosphopeptides on the size and shape of iron-iron oxide core-shell nanoparticles prepared in a one-pot synthesis by sodium borohydride reduction of an iron salt. These phosphopeptides are effective at small ratios of peptide to metal, in contrast to the behaviour of conventional capping agents, which must be added at high concentration to control the particle growth.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0MD00172D
Abstract: Lipidated Peptide5 analogues are able to mediate hemichannel openings leading to inhibition of chemical messengers to the extracellular matrix.
Publisher: American Chemical Society (ACS)
Date: 08-12-2022
Publisher: Elsevier BV
Date: 06-2007
Publisher: American Chemical Society (ACS)
Date: 22-07-2019
DOI: 10.1021/ACS.BIOCHEM.9B00571
Abstract: Adrenomedullin 2 (AM2) is a peptide hormone with potent effects in the cardiovascular system. The N-terminal disulfide loop of AM2 is thought to be important for interacting with its receptors to initiate a signaling response. However, the relative contribution of each amino acid within this region is currently unknown. Thus, the region was investigated using an alanine scanning approach. Two AM2 peptides (AM2-47 and AM2-40) were directly compared at the CGRP, AM
Publisher: American Chemical Society (ACS)
Date: 07-06-2017
DOI: 10.1021/ACS.JNATPROD.7B00314
Abstract: The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis features a key Maillard-type condensation of a complex amine derived from cis-4-hydroxy-l-proline with a dihydropyranone, to directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis of optical rotation data obtained for the synthesized compound.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00822K
Abstract: The facile preparation of cell-targeted platinum nanoparticles (PtNPs) is described, using designed peptides that as a single molecule control PtNP cluster growth, stabilise clusters in aqueous suspension and enable attachment of a versatile range of cell-targeting ligands.
Publisher: Wiley
Date: 27-05-2020
Publisher: MDPI AG
Date: 06-07-2022
DOI: 10.3390/MOLECULES27144331
Abstract: A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in blood caused by rapid renal excretion and its reported high susceptibility to serum proteases. The incorporation of poly (ethylene glycol) chains, coined PEGylation, is a well-established approach to improve the pharmacokinetic properties of drug molecules. Here, we report a systematic study on the incorporation of a varying number of ethylene glycol units (1–20) into the A20FMDV2 peptide to establish the effects of PEGylation size on the peptide stability in both rat serum and human plasma. In addition, the effect of acetyl and propionyl PEGylation handles on peptide stability is also described. Selected peptide analogues were assessed for integrin-αvβ6-targeted binding, showing good specificity and activity in vitro. Stability studies in rat serum established that all of the PEGylated peptides displayed good stability, and an A20FMDV2 peptide containing twenty ethylene glycol units (PEG20) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG2 and PEG5) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0QO00624F
Abstract: This review summarized the enzymatic and non-enzymatic crosslinks found in collagen and elastin and their organic synthesis.
Publisher: Wiley
Date: 2006
DOI: 10.1002/JLCR.1075
Publisher: Georg Thieme Verlag KG
Date: 11-06-2012
Publisher: American Chemical Society (ACS)
Date: 15-01-2015
DOI: 10.1021/OL503507G
Abstract: The first total synthesis of YM-280193, a cyclic depsipeptide that inhibits the ADP-induced aggregation of human platelets, is described. The monomer and dipeptide fragments were prepared using conventional chemistry and subsequently assembled by Fmoc-solid-phase peptide synthesis (Fmoc-SPPS). A late-stage novel bis-alkylation-elimination of cysteine on-resin was employed to introduce the unnatural N-methyldehydroalanine moiety. The final step involved execution of a key macrolactamization reaction between the hindered unnatural N,O-dimethylthreonine and β-hydroxyleucine residues.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9MD00050J
Abstract: The first syntheses of the bioactive cyclic tetrapeptide natural products, endolides A and B, were accomplished using a solution-phase macrocyclisation reaction the stereoselectivity of which was found to be reagent-controlled.
Publisher: American Chemical Society (ACS)
Date: 04-03-2019
DOI: 10.1021/ACS.ACCOUNTS.8B00624
Abstract: The alarming rate at which micro-organisms are developing resistance to conventional antibiotics represents one of the global challenges of our time. There is currently le space in the antibacterial drug pipeline, and scientists are trying to find innovative and novel strategies to target the microbial enemies. Nature has remained a source of inspiration for most of the antibiotics developed and used, and the immune molecules produced by the innate defense systems, as a first line of defense, have been heralded as the next source of antibiotics. Most living organisms produce an arsenal of antimicrobial peptides (AMPs) to rapidly fend off intruding pathogens, and several different attempts have been made to transform this versatile group of compounds into the next generation of antibiotics. However, faced with the many hurdles of using peptides as drugs, the success of these defense molecules as therapeutics remains to be realized. AMPs derived from the proteolytic degradation of the innate defense protein lactoferrin have been shown to display several favorable antimicrobial properties. In an attempt to investigate the biological and pharmacological properties of these much shorter AMPs, the sequence dependence was investigated, and it was shown, through a series of truncation experiments, that these AMPs in fact can be prepared as tripeptides, with improved antimicrobial activity, via the incorporation of unnatural hydrophobic residues and terminal cappings. In this Account, we describe how this class of promising cationic tripeptides has been developed to specifically address the main challenges limiting the general use of AMPs. This has been made possible through the identification of the antibacterial pharmacophore and via the incorporation of a range of unnatural hydrophobic and cationic amino acids. Incorporation of these residues at selected positions has allowed us to extensively establish how these compounds interact with the major proteolytic enzymes trypsin and chymotrypsin and also the two major drug-binding plasma proteins serum albumin and α-1 glycoprotein. Several of the challenges associated with using AMPs relate to their size, susceptibility to rapid proteolytic degradation, and poor oral bioavailability. Our studies have addressed these issues in detail, and the results have allowed us to effectively design and prepare active and metabolically stable AMPs that have been evaluated in a range of functional settings. The optimized short AMPs display inhibitory activities against a plethora of micro-organisms at low micromolar concentrations, and they have been shown to target resistant strains of both bacteria and fungi alike with a very rapid mode of action. Our Account further describes how these compounds behave in in vivo experiments and highlights both the challenges and possibilities of the intriguing compounds. In several areas, they have been shown to exhibit comparable or superior activity to established antibacterial, antifungal, and antifouling commercial products. This illustrates their ability to effectively target and eradicate various microbes in a variety of settings ranging from the ocean to the clinic.
Publisher: American Chemical Society (ACS)
Date: 13-06-2013
DOI: 10.1021/MA400803J
Publisher: Elsevier BV
Date: 05-2000
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.BMCL.2013.10.046
Abstract: A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20 compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SM01071E
Abstract: Increased water solubility and long-range intermolecular ordering have been introduced into the fluorescent organic molecule thiophene-diketopyrrolopyrrole via its conjugation to the octapeptide HEFISTAH, derived from a protein–protein β-interface.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00160A
Abstract: Two analogues of insulin glargine containing a 1,4-disubstituted 1,2,3-triazole group in place of the CysA7–CysB7 disulfide bond were prepared using CuAAC click chemistry to efficiently join the peptide chains.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.BMC.2008.04.037
Abstract: The naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB00112F
Abstract: Un-protected 2-acetamido terminated reducing sugars may be converted into the corresponding glycosyl thiols in water, and conjugated to peptides using the thiol–ene click reaction without recourse to any protecting groups.
Publisher: Elsevier BV
Date: 11-1998
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3OB01469J
Publisher: Wiley
Date: 2007
DOI: 10.1002/MRC.2027
Abstract: The 1H and 13C NMR data for 3-azabicyclo[3.3.1]nonanes having C-1 methylsuccinimidoanthranilate esters and C-6 methyl ethers were measured and assigned using 1D (DEPT) and 2D (COSY, HSQC, HMBC, NOESY) experiments. Comparison of this with previously published data illustrates the effects of stereochemistry and substitution on the basic heterocyclic framework.
Publisher: Georg Thieme Verlag KG
Date: 2012
Publisher: American Chemical Society (ACS)
Date: 10-10-2017
Abstract: The stereoselective access to stereotriads as important polyketide building blocks is reported on the basis of the Krische-type hydrogen-mediated syn-crotylation. The products were obtained with an extremely high diastereoselectivity (dr >99:1), and the newly formed syn stereocenters were controlled solely by the chiral catalyst. The stereochemistry was assigned by crystallography and HPLC for both product manifolds. This extension of the burgeoning transfer hydrogen methodology gives ergent asymmetric access to anti,syn and syn,syn polyketide stereotriads from the same α-chiral starting material and avoids potentially epimerizable aldehyde intermediates.
Publisher: Royal Society of Chemistry (RSC)
Date: 1988
DOI: 10.1039/C39880000978
Publisher: Elsevier BV
Date: 1988
Publisher: American Chemical Society (ACS)
Date: 11-2012
DOI: 10.1021/OL302745F
Abstract: The synthesis of advanced glycation endproducts (AGEs), CML, CEL, and pyrraline and their incorporation into collagen model peptides is reported. AGEs are modified amino acids that form on proteins such as collagen and are thought to play a significant role in the pathogenesis of many diseases, particularly diabetes. The synthesis and incorporation of these compounds into synthetic peptides is a key step in developing model systems with which to investigate AGE-modified proteins.
Publisher: Elsevier BV
Date: 10-1991
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CS00115E
Abstract: This review comprehensively summarizes various types of fluorescent probes for PD and their applications for detection of various PD biomarkers.
Publisher: Royal Society of Chemistry (RSC)
Date: 2200
DOI: 10.1039/C4CC02003K
Abstract: Cross-linking lysyl AGEs were synthesised and incorporated into two types of collagen peptides and now enable detailed analysis of the effects these cross-links have on biological systems.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.BMC.2007.02.012
Abstract: Norbormide [5-(alpha-hydroxy-alpha-2-pyridylbenzyl)-7-(alpha-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. A series of NRB-related analogues were prepared to investigate the structural features responsible for, and the in vitro biological markers indicative of, in vivo lethality of the parent molecule in rats. Their synthesis and biological evaluation (vasoconstriction, vasodilation, mitochondrial dysfunction, cardiotoxicity and lethality) is described.
Publisher: Wiley
Date: 07-10-2009
Publisher: Informa UK Limited
Date: 22-03-2012
DOI: 10.3109/10837450.2012.668554
Abstract: The study was aimed at determining the acid dissociation constant of cryptolepine hydrochloride and its degradation under stressed conditions. The pKa was determined using buffers in the pH range 10.4-11.6 by spectrophotometry at controlled measurement temperature (20 ± 0.5°C). The stability of the compound was investigated under various stressed conditions including neutral, acid, alkaline, light, dry heat and oxidation at different temperatures. Degradation products were analysed by HPLC. The calculated pKa values (uncorrected and corrected for ionic strength) were 11.09 ± 0.03 and 10.99 ± 0.05, respectively. A graphical approach yielded an uncorrected pKa value of 11.07. Degradation of the compound in water, 0.1 M HCl, 0.1 M NaOH and 3% hydrogen peroxide followed a first order reaction. With proper temperature control and maintenance of uniform ionic strength, a reproducible pKa of cryptolepine is obtainable by spectrophotometry. The compound was found to be highly susceptible to oxidation and relatively stable in neutral and acidic conditions but less so in a basic medium. There were no significant changes in concentration of s les exposed to light and dry heat at 60°C over the study period.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH13035
Abstract: Twenty nine novel spiroketal derivatives related to the rubromycins were evaluated for their anti-telomerase activity using the real-time quantitative telomeric repeat lification protocol assay. The parent compound γ-rubromycin exhibited the highest potency against human telomerase activity within the series. Modification of the spiroketal motif by the introduction of heteroatoms and substituents at different positions produced analogues with varying bioactivity. Variation at the isocoumarin subunit of the title compound resulted in weaker activity, indicative of its importance in telomerase inhibition.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.BMC.2014.05.026
Abstract: Preptin, a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. We have previously established that a shorter fragment of preptin, namely preptin-(1–16), stimulates bone growth by proliferation and increasing the survival rate of osteoblasts. This was demonstrated in both in vitro and in vivo models. These findings suggest that preptin-(1–16) could play an important role in the anabolic therapy of osteoporosis. However, due to the large size of the peptide it is not an ideal therapeutic agent. The aim of this study was to identify the shortest preptin analogue that retains or even increases the bone anabolic activity as compared to the parent preptin-(1–16) peptide. Truncations were made in a methodical manner from both the N-terminus and the C-terminus of the peptide, and the effect of these deletions on the resulting biological activity was assessed. In order to improve the enzymatic stability of the shortest yet active analogue identified, ruthenium-catalysed ring closing metathesis was used to generate a macrocyclic peptide using allylglycine residues as handles for ring formation. We have successfully identified a short 8-amino acid preptin (1–8) fragment that retains an anabolic effect on the proliferation of primary rat osteoblasts and enhances bone nodule formation. Preptin (1–8) is a useful lead compound for the development of orally active therapeutics for the treatment of osteoporosis.
Publisher: Elsevier BV
Date: 07-1996
Publisher: Elsevier
Date: 2009
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.BMC.2009.08.064
Abstract: A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a erse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2008
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Chemical Society (ACS)
Date: 08-04-2020
Publisher: American Chemical Society (ACS)
Date: 12-01-2012
DOI: 10.1021/OL203407Z
Abstract: We herein describe the first synthesis of the native antimicrobial protein HBD-1 making use of an orthogonal thiol protection strategy and a novel dicarba analogue thereof. The robust hydrocarbon linkage was installed by replacement of one disulfide bond using on-resin ring closing metathesis. The unprecedented 59-membered C-terminal cysteine macrocyclic fragment thus formed then engages in native chemical ligation allowing convergent access to this unique synthetic protein analogue.
Publisher: Georg Thieme Verlag KG
Date: 28-11-2011
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7SC04383J
Abstract: Replacing the O -linked saccharide in the bacteriocin glycocin F with an S -linked version results in a peptidomimetic that increases the bacteriostatic effect.
Publisher: Elsevier BV
Date: 06-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC01814G
Abstract: We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0CS00354A
Abstract: Thiol–ene chemistry, a tailored approach to access novel peptide-based drugs.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4SC03599B
Abstract: Glycolipid–peptide conjugates designed to release vaccine components within target cells ensuring potent CD1d dependent T cell responses.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 10-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3CC44717K
Abstract: An efficient synthesis of racemic or optically active α-amino acids by modified-Mitsunobu alkylation of a racemic or chiral glycine template from alcohols was developed. Libraries of amino acids were prepared in moderate to good yield with good to high enantioselectivity. This simple method widens the scope for preparation of structurally erse amino acids.
Publisher: American Chemical Society (ACS)
Date: 05-11-2012
DOI: 10.1021/OL302852Q
Abstract: The postulated structure of the potent anticancer peptaibol culicinin D has been synthesized using Fmoc-based solid-phase peptide synthesis (SPPS). Comparison of the (1)H NMR data for the reported structure of culicinin D with the data obtained for the two synthetic polypeptides epimeric at C-6 in the AHMOD unit established the C-6 stereochemistry of the AHMOD residue in the natural product to be (R).
Publisher: Wiley
Date: 19-03-2014
Publisher: American Chemical Society (ACS)
Date: 12-09-2017
DOI: 10.1021/ACS.ORGLETT.7B02687
Abstract: The total synthesis of the 2-nitropyrrole natural products nitropyrrolins A and B and the formal synthesis of nitropyrrolin D are reported. The key 2-nitro-4-alkylpyrrole core was efficiently assembled by Sonogashira cross-coupling, with complete control of regioselectivity. An unusual carboxylative cyclization, sulfonylcarbamate formation, and base-promoted cleavage sequence enabled access to the key hydroxy ketone without affecting the protected 2-nitropyrrole unit. The total synthesis provides a general approach for preparation of the bioactive nitropyrrolin family of natural products.
Publisher: International Union of Crystallography (IUCr)
Date: 11-03-2005
Publisher: Wiley
Date: 04-05-2016
Abstract: Proteins from the GASA/snakin superfamily are common in plant proteomes and have erse functions, including hormonal crosstalk, development, and defense. One 63-residue member of this family, snakin-1, an antimicrobial protein from potatoes, has previously been chemically synthesized in a fully active form. Herein the 1.5 Å structure of snakin-1, determined by a novel combination of racemic protein crystallization and radiation-damage-induced phasing (RIP), is reported. Racemic crystals of snakin-1 and quasi-racemic crystals incorporating an unnatural 4-iodophenylalanine residue were prepared from chemically synthesized d- and l-proteins. Breakage of the C-I bonds in the quasi-racemic crystals facilitated structure determination by RIP. The crystal structure reveals a unique protein fold with six disulfide crosslinks, presenting a distinct electrostatic surface that may target the protein to microbial cell surfaces.
Publisher: American Chemical Society (ACS)
Date: 05-04-2013
DOI: 10.1021/OL400686F
Abstract: A highly convergent synthesis of the griseusin B scaffold is described. The key step involves an efficient one-pot Hauser-Kraus annulation-methylation-double deprotection-spirocyclization sequence that directly affords the target parent tetracyclic ring system.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BMC.2012.02.035
Abstract: Our continuing programme aiming at developing inhibitors of integrin α4β7, a key mediator of various inflammatory diseases, led us to synthesise a library of cell-permeable peptides based on the biotin-R(8)ERY(∗) template, wherein the tyrosine residue has been modified by using the CuAAC reaction. The peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn(2+)-activated adhesion of mouse TK-1 T cells to mouse MAdCAM-1. Two of the synthesised peptidomimetics, analogues 11 and 14, are more active than our previously reported lead compound biotin-r(9)YDRREY at concentrations of 100 and 50 μM, with 14 exhibiting an IC(50) of less than 10 μM.
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Chemical Society (ACS)
Date: 31-12-2008
DOI: 10.1021/OL8025457
Abstract: A novel approach to the CDE fragment of pectenotoxin-4 is described wherein the bicyclic acetal is constructed via a cascade cyclization induced by VO(acac)(2) epoxidation of a homoallylic alcohol.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.BMC.2012.02.030
Abstract: Osteoporotic fracture is a significant public health problem, resulting in fractures in >50% of women and in almost one third of men age 65 and older. Most of the existing therapies act by slowing bone loss, through inhibiting the action of bone resorbing cells. However, more substantial reductions of fracture numbers will only result from treatments that can rebuild bone. Our own animal studies demonstrated the anabolic potential of the small but unstable octapeptide fragment of amylin-(1-37), namely amylin-(1-8) containing one disulfide bridge (Cys/2 and Cys/7) [Am. J. Physiol. Endocrinol. Metab.2000, 279, E730]. Herein, we describe the synthesis of amylin-(1-8) octapeptide and seven analogues thereof wherein the disulfide bridge is modified either via insertion of different linkers or bridges of a different nature in order to improve the stability and/or bone anabolic activity of the parent peptide. The peptide analogues were screened for proliferative activity in primary foetal rat bone-forming cells or osteoblasts at physiological concentrations. One such analogue showed promising biological activity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0OB00950D
Abstract: Thiol–ene CLipPA reaction of a vinyl ester and thiolated peptide for generation of an S -lipidated paenipeptin C′ analogue with broad spectrum antibacterial activity.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Elsevier BV
Date: 10-2011
Publisher: Elsevier BV
Date: 06-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B600951D
Abstract: The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.
Publisher: American Chemical Society (ACS)
Date: 04-05-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2007
DOI: 10.1039/B700307M
Abstract: An overview of the structure and biological activity of macrocyclic polyketides derived from dinoflagellates that contain unusual cyclic imine units is provided. The total and partial syntheses of these molecules are discussed with an emphasis on the construction of the spiroimine functionality thought to be the key pharmacophore of these fact-acting shellfish toxins.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Georg Thieme Verlag KG
Date: 31-07-2009
Publisher: Georg Thieme Verlag KG
Date: 24-08-2009
Publisher: Wiley
Date: 26-11-2007
DOI: 10.1002/MRC.2100
Abstract: The 1H and 13C NMR data for 3-azabicyclo[3.3.1]nonanes with OH and OMe substituents at C-6 and C-9 were measured using 1D (DEPT) and 2D (COSY, HSQC, HMBC, NOESY) experiments. Comparison of this NMR data illustrates the effects of stereochemistry and substitution at these positions.
Publisher: Georg Thieme Verlag KG
Date: 19-02-2020
Abstract: Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N,N′-dioxide–nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C5–C6 disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2OB01992B
Abstract: This work details a novel approach to access the [7,6]-spirocyclic fragment of 13-desmethyl spirolide C. A more efficient synthesis of the key lactam dienophile is reported, and a comprehensive investigation of the Diels-Alder reaction is included.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.BMCL.2012.06.015
Abstract: With over a 100 different serotypes, the human rhinovirus (HRV) is the major aetiological agent for the common cold, for which only symptomatic treatment is available. HRV maturation and replication is entirely dependent on the activity of a virally encoded 3C protease that represents an attractive target for the development of therapeutics to treat the common cold. Although a variety of small molecules and peptidomimetics have been found to inhibit HRV 3C protease, no universally compatible assay exists to reliably quantify the activity of the enzyme in vitro. Herein we report the development of a universal and robust solid phase peptide assay that utilizes the full HRV-14 3C protease recognition sequence and the release of 5(6)-carboxyfluorescein to sensitively quantify protease activity. This novel assay overcomes several limitations of existing assays allowing for the simple and efficient analysis of HRV-14 3C protease activity facilitating both high-throughput screening and the accurate kinetic study of HRV-14 3C protease inhibitors.
Publisher: Wiley
Date: 18-03-2014
Abstract: Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine-rich snakin-1 and -2 antimicrobial peptides by using a combination of solid-phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40-50 % yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin-2 compared to natural snakin-2, we demonstrated that synthetic snakin-2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin-2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds.
Publisher: American Chemical Society (ACS)
Date: 26-02-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7SC01647F
Abstract: A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological pH, based upon 3 a -bromo-norborn-2-en-7-one Diels–Alder cycloadducts has been developed.
Publisher: American Chemical Society (ACS)
Date: 06-2005
DOI: 10.1021/OL0507975
Abstract: [reaction: see text] A highly stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing fragment 5 of PTX7 (4) has been achieved. Appendage of the C ring to the AB fragment involved Wittig reaction of spiroacetal aldehyde 8 with a stabilized ylide 9 followed by displacement of allylic iodide 27 with a lithium acetylide to afford enyne 7. Fructose-derived chiral dioxirane and dihydroxylation were then used to introduce the correct functionality in the tetrahydrofuran C ring.
Publisher: Wiley
Date: 07-2014
DOI: 10.1002/BIP.22501
Abstract: The chemical synthesis is described of a polypeptide construct possessing both the variable and the collagen-like domain of adiponectin, which can be used as a model system for probing the influence of the variable domain on multimerization of this important circulating hormone. Using a collagen domain repeat peptide unit derived from native adiponectin or a glutamic acid analogue was ineffective due to noncollagenous conformational properties in both cases. However, employing a collagen model peptide and linking this to the variable domain thioester peptide using native chemical ligation proved effective. The 63 residue peptide was characterized by circular dichroism and mass spectrometry which demonstrated that a collagen-like triple-helical structure was preserved.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7CC05025A
Abstract: Advanced lipid peroxidation end-products (ALEs) accumulate with ageing and oxidative stress-related diseases.
Publisher: Elsevier BV
Date: 02-2001
Publisher: International Union of Crystallography (IUCr)
Date: 04-12-2004
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.BMC.2014.02.013
Abstract: A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
Publisher: Wiley
Date: 14-01-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB00496F
Abstract: This review summarises the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7NP00049A
Abstract: This review compiles details of the isolation, proposed biogenesis and biological testing of a new family of marine sesterterpenoids isolated around the Pacific Rim between 2009–2017.
Publisher: Wiley
Date: 07-09-2020
Publisher: Elsevier BV
Date: 07-1998
Publisher: American Chemical Society (ACS)
Date: 18-07-2019
DOI: 10.1021/ACS.JNATPROD.9B00351
Abstract: Natural products containing a lumazine motif were first isolated from natural sources in 1940. These natural products are relatively rare, with fewer than 100 lumazines known to occur in Nature. This review discusses the isolation of lumazines, their biological activity, and their biosynthesis, where known.
Publisher: Elsevier BV
Date: 10-2005
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.EJMECH.2014.11.038
Abstract: Since the first reported synthesis of an α-carboline almost a century ago, there has been a steady interest in the development of strategies towards this unique heterocyclic motif. This interest can mainly be attributed to a range of biological activity displayed by the α-carboline natural products including cytotoxicity, anticancer properties or CNS activity. Numerous studies have led to the development of a number of alternative methods to prepare simple α-carbolines as well as a range of synthetic α-carboline derived compounds.
Publisher: Elsevier BV
Date: 10-2005
Publisher: American Chemical Society (ACS)
Date: 26-02-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2004
DOI: 10.1039/B412883D
Abstract: The synthesis of the 1,6,8-trioxadispiro[4.1.5.2]tetradec-11-enes 12 present in the shellfish toxins spirolides B and D 2, is reported. The two spirocentres were constructed via iterative radical oxidative cyclization of hydroxyalkyl dihydropyran 14 and hydroxyalkyl spiroacetal 13 using iodobenzene diacetate and iodine. This procedure initially afforded a 1 : 1 : 1 : 1 mixture of bis-spiroacetals 12a : 12b : 12c : 12d, however subsequent acid catalysed equilibration afforded a 3 : 1 : 0.9 thermodynamic mixture of 12a : 12b : 12c. The major bis-spiroacetal 12a underwent stereoselective epoxidation using dimethyldioxirane to alpha-epoxide 33a. Subsequent base induced rearrangement of this epoxide 33a using lithium diethylamide in pentane afforded allylic alcohol 34a, that was converted to the more thermodynamically favoured homoallylic alcohol 11a upon treatment with lithium pyrrolidinylamide in tetrahydrofuran. Homoallylic alcohol 11a possesses a hydroxyl group at C-12 as required for introduction of the tertiary alcohol group present at this position in spirolides B 1 and D 2.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3CC41751D
Abstract: Herein we report the rational design of new phosphopeptides for control of nucleation, growth and aggregation of water-soluble, superparamagnetic iron-iron oxide core-shell nanoparticles. The use of the designed peptides enables a one-pot synthesis that avoids utilizing unstable or toxic iron precursors, organic solvents, and the need for exchange of capping agent after synthesis of the NPs.
Publisher: American Chemical Society (ACS)
Date: 27-11-2012
DOI: 10.1021/OL302536J
Abstract: A synthetic approach to the tetracyclic core of berkelic acid is reported using gold(I)-catalyzed intramolecular hydroarylation and oxidative radical cyclizations to effect the key ring-forming steps. The carboxylic acid was introduced via a late-stage palladium-catalyzed carbonylation to afford the core tetracycle with the correct relative stereochemistry for the natural product.
Publisher: American Chemical Society (ACS)
Date: 21-10-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3OB00998J
Abstract: Synthesis of the spirocyclic core of portimines A and B was achieved utilizing a key Diels–Alder reaction of a bromodiene with a malonate dienophile.
Publisher: Georg Thieme Verlag KG
Date: 28-03-2008
Publisher: Royal Society of Chemistry (RSC)
Date: 2003
DOI: 10.1039/B309722F
Abstract: The synthesis of bis-furonaphthopyrans 12a and 12b, regioisomeric analogues of the dimeric pyranonaphthoquinone antibiotic crisamicin A 1 is described. The key intermediate 16 was prepared via a one-pot in situ Suzuki-Miyaura homocoupling of naphthyl triflate 23 using bis(pinacolato)diboron. Oxidation of binaphthyl 16 to bis-naphthoquinone 14 was then effected with silver(II) oxide and nitric acid. Efficient double furofuran annulation of bis-naphthoquinone 14 with 2-trimethylsilyloxyfuran 8 afforded bis-furonaphthofuran adducts 13a and 13b as an inseparable 1:1 mixture of diastereomers. Oxidative rearrangement of this mixture of bis-furonaphthofuran adducts 13a and 13b using silver(II) oxide and nitric acid afforded unstable bis-furonaphthopyrans 12a and 12b also as a 1:1 mixture of diastereomers. Addition of 2-trimethylsilyloxyfuran 8 to naphthoquinone 25 afforded adduct 26 that underwent oxidative rearrangement to furonaphthopyran 27, however attempts to effect Suzuki-Miyaura homocoupling of triflates 26 and 27 to their respective dimers 13 and 12, was unsuccessful.
Publisher: International Union of Crystallography (IUCr)
Date: 30-04-2004
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1OB06394D
Abstract: The synthesis of naturally occurring glycosylated (2S,5R)-hydroxylysine still remains a challenge. This perspective highlights the importance of this post-translationally modified amino acid residue in the observed bioactivity of collagen and related collagen-like proteins such as adiponectin, an important target for the treatment of type II diabetes. Strategies employed to date for the syntheses of (2S,5R)-hydroxylysine and the methods to effect glycosylation of this modified amino acid are also summarized herein.
Publisher: Royal Society of Chemistry (RSC)
Date: 2003
DOI: 10.1039/B301449P
Abstract: The synthesis of an isomeric mixture of 4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl analogues 6 of the C-glycosylpyranonaphthoquinone antibiotic medermycin is described. The key 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 8 was prepared via Stille coupling of 6-(3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3-bromo-1,4- naphthoquinone 17 with (alpha-ethoxyvinyl)tributyl-stannane followed by hydrolysis and oxidation of the resultant hydroquinone 18. Bromonaphthoquinone 17 in turn was afforded by oxidative demethylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)-3- bromo-1,4,5-trimethoxynaphthalene 16 formed by regioselective bromination of 6-(4-acetyl-3-azido-2,3,6-trideoxy- beta-D-arabino-hexopyranosyl)-1,4,5-trimethoxynaphthalene 10. This latter naphthalene 10 was prepared via direct C-glycosylation of naphthol 12 with glycosyl donor 11 using BF3.Et2O in acetonitrile. The regioselectivity of the bromination of naphthalene 10 was independently determined by reductive monomethylation of the 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-5-methoxy-1,4-naphthoquinone 22 to naphthol 23 followed by selective ortho bromination to bromide 24 and methylation to 16. Attempts to effect acetylation of 6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-3-bromo-1,4,5-trimethoxynaphthalene 16 and 3-bromo-6-(3-dimethylamino-2,3,6-trideoxy-beta-D-arabino- hexopyranosyl)-1,4,5-trimethoxynaphthalene 26 via Stille coupling with (alpha-ethoxyvinyl)tributylstannane were low yielding thereby establishing the necessity to use an azido group as a latent dimethylamino group and a more electrophilic bromonaphthoquinone as the coupling partner for the Stille reaction. Addition of 2-trimethylsilyloxyfuran 9 to 3-acetyl-6-(4-O-acetyl-3-azido-2,3,6-trideoxy-beta-D-arabino-hexopyranosyl)- 5-methoxy-1,4-naphthoquinone 8 afforded the furofuran adducts 7 and 19 as an inseparable mixture of diastereomers. Oxidative rearrangement of this diastereomeric mixture using ceric ammonium nitrate afforded the inseparable diastereomeric furonaphthopyrans 6 and 20.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.CARRES.2007.08.015
Abstract: The synthesis of Nalpha-fluorenylmethoxycarbonyl-trans-4-hydroxy-4-O-[(2,3,4,6-tetra-O-acetyl)-alpha-d-mannopyranosyl]-l-proline allyl ester and Nalpha-fluorenylmethoxycarbonyl-trans-4-hydroxy-4-O-[(2,3,4,6-tetra-O-benzoyl)-alpha-d-mannopyranosyl]-l-proline allyl ester is described. Glycosylation using Königs-Knorr conditions with a benzoyl protected glycosyl donor provided the optimum method. Removal of the allyl ester gave two mannosylated building blocks suitable for solid phase glycopeptide synthesis.
Publisher: Elsevier BV
Date: 07-2009
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/CH14513
Abstract: The objective of this research was to develop novel phosphonate-containing polymers as they remain a relatively under researched area of polymer chemistry. Herein, we report the synthesis and characterization of 2-(1-(2-(diethoxyphosphoryl)ethyl)-1H-1,2,3-triazol-4-yl)ethyl acrylate (M1) and diethyl (2-(4-(2-acrylamidoethyl)-1H-1,2,3-triazol-1-yl)ethyl)phosphonate (M2) monomers using the copper-catalyzed azide–alkyne cycloaddition (CuAAC) ‘click’ reaction, and their subsequent polymerization via both uncontrolled and reversible addition–fragmentation chain transfer (RAFT) polymerization techniques yielding phosphonate polymers (P1–P4).
Publisher: Wiley
Date: 24-08-2009
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.BBABIO.2011.08.007
Abstract: We have investigated the mechanism of rat-selective induction of the mitochondrial permeability transition (PT) by norbormide (NRB). We show that the inducing effect of NRB on the PT (i) is inhibited by the selective ligands of the 18kDa outer membrane (OMM) translocator protein (TSPO, formerly peripheral benzodiazepine receptor) protoporphyrin IX, N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one and (ii) is lost in digitonin mitoplasts, which lack an intact OMM. In mitoplasts the PT can still be induced by the NRB cationic derivative OL14, which contrary to NRB is also effective in intact mitochondria from mouse and guinea pig. We conclude that selective NRB transport into rat mitochondria occurs via TSPO in the OMM, which allows its translocation to PT-regulating sites in the inner membrane. Thus, species-specificity of NRB toward the rat PT depends on subtle differences in the structure of TSPO or of TSPO-associated proteins affecting its substrate specificity.
Publisher: American Chemical Society (ACS)
Date: 17-04-2023
Publisher: Elsevier BV
Date: 2002
Publisher: Georg Thieme Verlag KG
Date: 2004
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B927219B
Abstract: The one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer.
Publisher: American Chemical Society (ACS)
Date: 14-09-2011
DOI: 10.1021/OL202265G
Abstract: An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.
Publisher: Wiley
Date: 2015
DOI: 10.1002/BIP.22600
Abstract: The chemical synthesis of analogue of a novel γ-secretase activating protein, which may play a pivotal role in the formation of amyloid peptides, the precursor to Alzheimer's disease, is described. The linear polypeptide sequence, consisting of 121 amino acids was assembled from four unprotected peptide building blocks using a convergent ligation-based synthesis. A strategic mutation of three glutamine residues to cysteine enabled the ligations, and the cysteines were subsequently converted to pseudoglutamines, to mimic the native glutamine. The full length unfolded protein was obtained in milligram amounts and was demonstrated to be homogeneous by liquid chromatography and mass spectrometry.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB01043J
Abstract: The first synthesis of click neoglycopeptide analogues of the biologically relevant MUC1 sequence is reported. In the process, microwave-enhanced chaotrope-assisted click reaction conditions that may be used on a routine basis for the synthesis of click peptide conjugates have been developed. The convergent route for the synthesis of neoglycopeptides using these reaction conditions enables the facile, rapid, and highly efficient preparation of focused neoglycopeptide libraries of defined chemical structure for biological evaluation.
Publisher: Elsevier BV
Date: 07-2010
Publisher: American Chemical Society (ACS)
Date: 20-10-2009
DOI: 10.1021/OL902131N
Abstract: The powerful combination of native chemical ligation and click chemistry has been used to affect a one-pot synthesis of neoglycopeptides from propargyl-containing peptides using GalNAc-N(3) as the glycan component. A versatile chemical toolkit for the fully convergent synthesis of neoglycoproteins using click chemistry, native chemical ligation, and kinetically controlled ligation is thus demonstrated.
Publisher: Elsevier BV
Date: 08-2002
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9QO00769E
Abstract: Intramolecular Diels–Alder [4 + 2] cycloaddition using a chiral Evans oxazolidinone auxiliary affords the trans -decalin framework of the potent antibiotic anthracimycin.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0OB00942C
Abstract: We review the structure–activity relationships and synthetic studies of TLR2 agonists – important chemical targets in immunotherapy.
Publisher: Wiley
Date: 15-08-2006
Publisher: Elsevier BV
Date: 07-2003
Publisher: Wiley
Date: 12-08-2013
Abstract: A radical lipidation: Application of a novel thiol-ene lipidation enables the one-step synthesis of self-adjuvanting antigenic peptides as vaccine candidates. The resultant monoacyl lipopeptides are shown to activate monocytes in a robust manner.
Publisher: Wiley
Date: 21-01-2015
Abstract: The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S-linked N-acetylglucosamine (GlcNAc) moiety in addition to an O-linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue.
Publisher: American Chemical Society (ACS)
Date: 28-11-2011
DOI: 10.1021/JO201988M
Abstract: The full details of our enantioselective formal synthesis of the biologically active natural product berkelic acid are described. The insertion of the C-18 methyl group proved challenging, with three different approaches investigated to install the correct stereochemistry. Our initial Horner-Wadsworth-Emmons/oxa-Michael approach to the berkelic acid core proved unsuccessful upon translation to the natural product itself. However, addition of a silyl enol ether to an oxonium ion, followed by a one-pot debenzylation/spiroketalisation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single diastereoisomer.
Publisher: Wiley
Date: 29-02-2020
DOI: 10.1002/PEP2.24150
Publisher: CSIRO Publishing
Date: 2000
DOI: 10.1071/CH00111
Abstract: A new method has been established for the preparation of C 2-oxidized 5,5-spiroacetals, which are key intermediates for the synthesis of the bis-spiroacetal moiety of the spirolides. A bridged orthoester was used as a masked carboxylic acid in the preparation of these bicyclic oxaspirolactones. The synthesis of chiral lactone (12), a building block for the synthesis of the spirolides, is also reported. The two chiral centres in lactone (12) were assembled by addition of a chiral crotyl borane to an aldehyde. The structure of lactone (12) was determined by single-crystal X-ray diffraction orthorhombic space group P212121 (No. 19), a 12.437(2), b 23.881(4), c 7.545(1) Å, V 2240.9(5) Å3, R(F) 0.0460, and Rw(F) 0.0458.
Publisher: Elsevier BV
Date: 03-2003
Publisher: Wiley
Date: 20-03-2014
DOI: 10.1002/PSC.2627
Abstract: Members of the Chordopoxvirinae subfamily possess an unusual 11 protein entry-fusion complex (EFC) that is highly conserved and present in all species. The mode of action of this EFC is unknown, and the interactions of the constituent proteins are uncharacterised. Here, we present the chemical synthesis of membrane domain truncated linear constructs of two EFC proteins in orf virus, ORFV036 and 049. By using Boc solid phase peptide synthesis and native chemical ligation methods, these truncated proteins have been readily prepared in milligram quantities. These robust synthetic protocols allow ready access to these polypeptides to facilitate biological studies.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.BMC.2012.05.014
Abstract: Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality alatability in vivo) is described. Compound 19 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats.
Publisher: Georg Thieme Verlag KG
Date: 24-07-2013
Publisher: American Chemical Society (ACS)
Date: 17-08-2012
DOI: 10.1021/JO3013435
Abstract: The efficient synthesis of multivalent neoglycoconjugates of MUC1 is reported, which utilizes Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuACC) of azide-functionalized GlcNAc-centered neoglycotetrasaccharide clusters to the MUC1 peptide sequence that was equipped with a propargylglycine residue for "click chemistry". In turn the azido-GlcNAc-centered neoglycoclusters were assembled by reaction of a GlcNAc core containing peripheral propargyl functionalities with an appropriate azido-functionalized monosaccharide. The resulting suitably substituted tetrasaccharyl triazole cluster can be easily appended to a range of acetylene-functionalized peptides to produce neoglycoconjugates of biologically important glycopeptides. As proof of principle, the click neoglycoclusters prepared herein were ligated to the MUC1 peptide sequence.
Publisher: American Chemical Society (ACS)
Date: 16-08-2019
DOI: 10.1021/ACS.JMEDCHEM.9B01044
Abstract: Cancer immunotherapy has gained increasing attention due to its potential specificity and lack of adverse side effects when compared to more traditional modes of treatment. Toll-like receptor 2 (TLR2) agonists are lipopeptides possessing the
Publisher: Georg Thieme Verlag KG
Date: 26-07-2013
Publisher: Georg Thieme Verlag KG
Date: 03-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3SC02543H
Abstract: This review covers recent progress in tyrosine-selective cleavage, functionalization, and conjugation of peptides and proteins. Key applications of Tyr modification are highlighted, demonstrating its great potential for chemistry and biology.
Publisher: Georg Thieme Verlag KG
Date: 06-06-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0MD00241K
Publisher: Georg Thieme Verlag KG
Date: 03-2007
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.ACTBIO.2016.07.021
Abstract: The self-assembling peptide IKHLSVN, inspired by inspection of a protein-protein interface, has previously been reported as one of a new class of bio-inspired peptides. Here the peptide, dubbed littleSven, and modifications designed to probe the resilience of the sequence to self-assembly, is characterised. Although the parent peptide did not form a hydrogel, small modifications to the sequence (one side chain or an N-terminus modification) led to hydrogels with properties (eg. gelation time and rheology) that could be tuned by these small alterations. The results suggest that peptides derived from protein-protein interfaces are resilient to changes in sequence and can be harnessed to form hydrogels with controlled properties. Natural occurring self-assembly peptides are attractive building blocks for engineered bionanomaterials due to their biocompatibility and biodegradability. The bio-inspired self-assembly peptide, IKHLSVN, was used as a template to design peptides that readily formed hydrogels. The peptide sequence was specifically tuned to create a bionanomaterial with different properties that could be exploited downstream for a broad range of applications: nanowires, drug release, vaccine adjuvant, tissue engineering. We describe how small modifications to the parent peptide alter the amyloid-like characteristics and gel strength for each peptide.
Publisher: Elsevier BV
Date: 04-2000
Publisher: American Chemical Society (ACS)
Date: 15-09-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B916041H
Abstract: Although known for over a quarter of a century, the oxidative radical cyclisation route to spiroketals has found limited use in natural product synthesis in comparison to classical approaches. Its successful application in this field of research forms the subject of this perspective.
Publisher: American Chemical Society (ACS)
Date: 16-10-2009
DOI: 10.1021/JO901992Z
Abstract: Beta-methoxymethyl enecarbamates (e.g., 1) have been prepared in a single step from alpha-methoxy carbamates. In the presence of a mild Lewis acid, compound 1 underwent substitution with a variety of nucleophiles including indoles, electron-rich aromatics, silyl enol ethers, and 2-trimethylsilyloxyfuran.
Publisher: Royal Society of Chemistry (RSC)
Date: 2005
DOI: 10.1039/B418106A
Abstract: The first enantioselective synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether has been carried out in a convergent fashion by heterocycle-activated Julia olefination of a spiroacetal-containing sulfone fragment with a phthalide-containing aldehyde fragment. The total synthesis of (+)-spirolaxine methyl ether establishes the absolute stereochemistry of the natural product to be (3R,2''R,5''R,7''R).
Publisher: Wiley
Date: 25-05-2005
Publisher: BMJ
Date: 04-2020
Abstract: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence. Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity. The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4 + and CD8 + responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1) + /Human Leukocyte Antigen (HLA) class I + double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants. The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/CH12227
Abstract: The α4β7 integrin is a well‐known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes, and multiple sclerosis. The β7 subunit contains the cell adhesion regulatory domain (CARD) motif YDRREY within its cytoplasmic domain, which is an effective peptide agent for inhibiting T-cell adhesion. The synthesis of a library of cell-permeable β7 integrin inhibitors based on the shortened biotin-R8ERY (R8 = (l-arginine)8) motif is reported, wherein the tyrosine residue has been modified. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn2+-activated adhesion of mouse TK-1 T-cells to mouse MAdCAM-1. Several analogues exhibited improved activity to that of the tyrosine-containing lead compound 1 (biotin-R8ERY). Specifically, analogues 4, 10, and 22 bearing a 4-chloro, a 4-nitro, and a 3,3-diphenyl substituent showed an increase in activity of approximately two-fold compared with that of the initial lead compound. The six most active compounds of the tested series had IC50’s between 25 and 50 μM.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4MD00420E
Abstract: Compounds 14 and 62 were identified using virtual screening to inhibit autophagy. The expression levels of the LC3-II and p62 autophagy proteins were used. SAR analysis revealed another active compound 38 . Formation of autophagosomes was severely reduced upon dosing of 14 , 38 and 62.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH12347
Abstract: The formation of functional liposomes by the self assembly of a peptide– hiphile that comprises the neuroprotective tripeptide motif glycyl-prolyl-glutamic acid linked to a hydrophobic moiety is reported. The self-assembled peptide–lipid conjugate displays long range order and can be dispersed as nanometre sized particles.
Publisher: American Chemical Society (ACS)
Date: 23-04-2018
Publisher: Wiley
Date: 06-08-2018
Publisher: International Union of Crystallography (IUCr)
Date: 25-03-2005
Publisher: Wiley
Date: 30-09-2019
Abstract: A de novo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC
Publisher: Wiley
Date: 14-02-2018
Publisher: Wiley
Date: 07-09-2020
Publisher: Elsevier BV
Date: 06-2010
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1SC06216F
Abstract: A Tyr-selective peptide cleavage was reported using Dess–Martin periodinane. The cleavage generates an unprecedented hyperoxidized tyrosine motif in the C-terminal fragment and showed excellent site-specificity and broad scope for various peptides.
Publisher: Public Library of Science (PLoS)
Date: 09-06-2014
Publisher: Elsevier BV
Date: 07-1996
Publisher: Georg Thieme Verlag KG
Date: 08-04-2009
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/CH12018
Abstract: The thermochemical cascades for the bioreductive alkylation of DNA by kalafungin were calculated using density functional theory (DFT). Guanine (G) was used as a model nucleotide. According to the calculations both one- and two-electron reduction of kalafungin is possible in vivo. Furthermore, a clear pathway was found for both mono- and bis-alkylations of G with the former favoured. Alkylation at C-8 position of G is considerably more exothermic than on the N2-exocyclic amine. In the absence of experimentally identified adduct structures of kalafungin, the results presented here support the idea that this compound readily forms covalent bonds with DNA resulting in pro-mutagenic lesions.
Publisher: American Chemical Society (ACS)
Date: 23-05-2014
DOI: 10.1021/JO5008527
Abstract: A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CBPA.2018.12.007
Abstract: The biological activity and structural ersity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid and alkaloid natural product scaffolds for inspiration in the design and development of important new drug candidates.
Publisher: Elsevier BV
Date: 08-2010
Publisher: American Chemical Society (ACS)
Date: 14-07-2021
Publisher: Elsevier BV
Date: 07-2007
Publisher: Wiley
Date: 12-04-2021
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/CH13452
Abstract: We report the multistep synthesis and polymerisation of a novel aniline derivative with a pendant α-d-mannose substituent. The α-D-mannose functionality was successfully introduced before polymerisation via copper-catalysed azide alkyne click chemistry and the resulting monomer was polymerised using general oxidative polymerisation conditions, producing a water soluble mannosylated polyaniline. The polymer was characterised by several techniques and compared with standard polyaniline. The selective binding of the polymer to Concanavalin A (ConA) was successfully demonstrated by the precipitation of polymer–ConA aggregates. Potential applications of these novel polyaniline glycopolymers could include the development of electroactive biomaterials with the ability to bind mannose receptors, or as sensors for proteins or microbes.
Publisher: Elsevier BV
Date: 02-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2006
DOI: 10.1039/B604334H
Abstract: The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a-d underwent equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7.
Publisher: Georg Thieme Verlag KG
Date: 14-08-2012
Publisher: Wiley
Date: 30-03-2009
Abstract: The synthesis of AE and BE analogues of the alkaloid methyllycaconitine is reported. The analogues contain two key pharmacophores: a 2‐(2‐methylmaleimido)benzoate ester and a homocholine motif formed from a tertiary N ‐(3‐phenylpropyl)amine incorporated into either a 3‐azabicyclo[3.3.1]nonane (AE) or octahydroquinoline (BE) ring system. An additional aromatic group is introduced into the AE bicyclic system using a Horner–Wadsworth–Emmons reaction. The BE analogues are synthesised by a one‐pot cyclisation using ethyl α‐(bromomethyl)acrylate, a primary amine and cyclohexanone leading to an efficient assembly of an octahydroquinoline ring system that mimics the BE‐rings of methyllycaconitine. In both the AE and BE analogues, the key 2‐(2‐methylsuccinimido)benzoate ester pharmacophore is introduced by esterification of the alcohol precursors with 2‐(2‐methylmaleimido)benzoic acid ( 10 ) under Steglich conditions followed by hydrogenation over palladium on charcoal.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Publisher: Wiley
Date: 06-08-2018
Abstract: We report a new method herein coined SP-CLipPA (solid-phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono-S-lipidated peptides. This technique utilizes thiol-ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin-bound peptide. Advantages of SP-CLipPA include: ease of handling, conversions of up to 91 %, by-product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP-HPLC purification. To showcase the utility of SP-CLipPA, we synthesized a potent calcitonin gene-related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP
Publisher: Elsevier BV
Date: 08-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C005400N
Publisher: Cambridge University Press (CUP)
Date: 02-04-2012
DOI: 10.1017/S0954102012000119
Abstract: Evolutionary disparate Antarctic notothenioids and Arctic gadids have adapted to their freezing environments through the elaboration of essentially identical antifreeze glycoproteins (AFGPs). Here we show that this convergence of molecular identity, which evolved from unrelated parent genes, extends to convergence in physiological deployment. Both fish groups synthesize AFGPs in the exocrine pancreas from where they are discharged into the gut to inhibit the growth of ingested ice. Antifreeze glycoproteins not lost with the faeces are resorbed from the gut via the rectal epithelium, transported to the blood and ultimately secreted into the bile, from where they re-enter the gastrointestinal tract. Antifreeze glycoprotein recirculation conserves energy expenditure and explains how high levels of AFGPs reach the blood in notothenioids since, unlike Arctic gadids which also synthesize AFGP in the liver, AFGP secretion in notothenioids is directed exclusively towards the gastrointestinal lumen. Since AFGPs function by inhibiting ice crystal growth, ice must be present for them to function. The two fish groups are thus faced with an identical problem of how to deal with internal ice. Here we show that both accumulate AFGPs within ellipsoidal macrophages of the spleen, presumably adsorbed to phagocytosed ice crystals which are then held until a warming event ensues.
Publisher: Walter de Gruyter GmbH
Date: 10-11-2012
Abstract: With the goal of presenting information in the scientific literature clearly and unambiguously, a set of rules for the abbreviation of protecting groups has been developed. It is based on principles designed to be as descriptive and systematic as possible, but also sufficiently pragmatic and flexible so as to accommodate the most important current abbreviations.
Publisher: Wiley
Date: 14-05-2021
DOI: 10.1002/PEP2.24230
Abstract: ERp44, a chaperone of the protein disulfide isomerase (PDI) family cycles between the endoplasmic reticulum (ER) and cis ‐Golgi compartments to act on a cohort of disparate proteins either to ensure their proper cellular localization or for the quality control of the correct assembly. This process involves intermolecular disulfide bond formation between the client protein and the conserved Cys29 in ERp44. We had identified a 9‐amino acid peptide derived from an ERp44 client, adiponectin, as the motif interacting with ERp44 via a highly conserved cysteine (Cys39 of adiponectin). However, in order to reveal detailed insight into the mode of interaction, the generation of sizeable amounts of corresponding thiol‐liganded ERp44 was unsuccessful under ambient conditions. Here we describe the production of a bromopeptide variant of this peptide ligand that led to large amounts of a pure, complex of peptide sufficient for structural studies in which Cys29 of Erp44 is covalently linked via a stable thioether bond. This method can be potentially used to rapidly probe putative, short, interacting peptide regions in other ERp44 clients to reveal their, hitherto unknown, mechanism of interaction with ERp44.
Publisher: American Chemical Society (ACS)
Date: 16-01-2018
DOI: 10.1021/ACS.ORGLETT.7B03925
Abstract: The first total synthesis of the highly N-methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the C-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerization. The total synthesis has enabled confirmation of the proposed absolute configuration of natural jahanyne.
Publisher: Walter de Gruyter GmbH
Date: 13-01-2011
Abstract: Synthetic studies toward the spiroimine unit of the spirolide family of shellfish biotoxins are described. Several strategies for introduction of the C7, C29, and C32 stereocenters of the A,E-ring system of the spirolides are described, such as spironitrone formation, Birch reductive alkylation, and asymmetric Diels–Alder cycloadditions.
Publisher: Georg Thieme Verlag KG
Date: 04-01-2010
Publisher: American Chemical Society (ACS)
Date: 05-06-2023
Publisher: Georg Thieme Verlag KG
Date: 10-06-2021
Abstract: Preliminary results of the effect of hydrophobicity and halogenation on the cytotoxicity of the anticancer peptaibol culicinin D are reported. Building on previous work, the synthetically challenging (2S,4S,6R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid and (2S,4R)-2-amino-4-methyldecanoic acid building blocks were replaced with derivatives of l-phenylalanine and 2-aminodecanoic acid, respectively. Substitution of (2S,4S,6R)-2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid with l-4,4′-biphenylalanine yielded an analogue that was tenfold more potent than the natural product and was also the most hydrophobic analogue, as judged by an antiproliferative IC50 assay and logD calculations these results suggest that the potency of culicinin D may be governed by its hydrophobicity. However, the introduction of halogenated moieties into the peptide sequence generated analogues that were similarly potent, although not necessarily hydrophobic. Thus, the parameters regulating the cytotoxicity of culicinin D, and by extension other peptaibols, are multimodal and include both halogenation and hydrophobicity.
Publisher: Georg Thieme Verlag KG
Date: 08-01-2010
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01388D
Abstract: A striking decrease in thermal stability was observed upon incorporation of triazole-linked galactosylated-lysine into an adiponectin model peptide, suggesting possible applications of ‘click’ glycomimetics in bioengineering.
Publisher: Elsevier BV
Date: 1985
Publisher: Wiley
Date: 25-07-2012
DOI: 10.1002/PSC.2432
Abstract: Unquestionably, the purification of polypeptides by chromatographic methods is a considerable bottleneck in their preparation. Peptides synthesised by solid phase synthesis typically contain chromatographically similar impurities that complicate purification by reversed phase high performance liquid chromatography (HPLC) techniques. We report on the application of a slow gradient HPLC protocol that allows, in a single chromatographic step, the purification of hundreds of milligrammes of material. This technique was applied to an extensive collection of synthetic polypeptides some incorporating non-proteinogenic functionality. In all cases examined, the peptides were not only obtained in high purity peptides but were also recovered in multi-milligramme amounts.
Publisher: Elsevier BV
Date: 12-1997
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB02169K
Abstract: Six analogues of the potent lipopeptide antibiotic, teixobactin were prepared by Fmoc SPPS and their activities examined against Gram positive bacteria.
Publisher: Elsevier BV
Date: 2014
Publisher: Wiley
Date: 26-06-2006
Abstract: The synthesis of several ABE tricyclic analogues 5 , 31 and 32 of the alkaloid methyllycaconitine ( 1 ) is reported. The analogues contain two key pharmacophores: a tertiary N ‐(3‐phenylpropyl) substituent attached to a 3‐azabicyclo[3.3.1]nonane ring system and a 2‐(3‐methyl‐2,5‐dioxopyrrolidin‐1‐yl)benzoate ester. Double Mannich reaction of the cyclic β‐keto esters 6 and 1 7 with the bis(aminol) ether 7 using methyltrichlorosilane as an activating agent provided an efficient method for the construction of the 3‐azabicyclo[3.3.1]nonanes 8 and 18 . Ring‐closing metathesis of the derived dienes 11 , 19 , and 20 afforded the tricyclic ethers 12 , 21 , and 22 , respectively, the C‐8 ester of which was reduced to a hydroxymethyl group to form the ABE tricyclic analogues 13 , 23 , and 24 . Conversion of the alcohol 13 to the anthranilate ester 14 using N ‐(trifluoroacetyl)anthranilic acid followed by fusion with methylsuccinic anhydride afforded the analogue 5 containing the key N ‐(methylsuccinimido)anthranilate pharmacophore. In the case of the alcohols 23 and 24 the 2‐(3‐methyl‐2,5‐dioxopyrrolidin‐1‐yl)benzoate ester pharmacophore was appended by direct esterification with unsaturated acid 28 followed by hydrogenation to the ABE tricyclic compounds 33 and 34 . (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Publisher: Elsevier BV
Date: 12-1995
Publisher: Georg Thieme Verlag KG
Date: 09-2007
Publisher: Royal Society of Chemistry (RSC)
Date: 2000
DOI: 10.1039/A909243I
Publisher: International Union of Crystallography (IUCr)
Date: 19-07-2008
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7BM00512A
Abstract: We report the Zn 2+ -mediated hydrogel formation of a β-hairpin peptide that proceeded via an intermolecular metal- coordination mechanism.
Publisher: Elsevier BV
Date: 04-2008
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 02-2000
Publisher: Springer Science and Business Media LLC
Date: 27-02-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9OB00262F
Abstract: In situ generation and reaction of novel 5-membered N -tosyl cyclic α,β-unsaturated iminium ions from readily prepared stable precursors is demonstrated.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.BMC.2016.05.061
Abstract: Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI50 at 30nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50=296nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1OB00355K
Abstract: In this work, the synthesis of reactive oxygen species responsive mono S -lipidated peptide hydrogels via a photoinitiated thiol–ene reaction is reported.
Publisher: Wiley
Date: 31-10-2021
DOI: 10.1111/BPH.15700
Abstract: The pituitary adenylate cyclase‐activating peptide (PACAP) family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP‐responsive class B G protein‐coupled receptors: the PAC 1 , VPAC 1 and VPAC 2 receptors. The PAC 1 receptor may be alternatively spliced, generating variants that can differ in their pharmacological or signalling profiles. To inform drug discovery efforts targeting migraine, we need to better understand how the different PACAP‐responsive receptors signal and how effectively these responses can be blocked by antagonists. The signalling profiles of the human PAC 1n , PAC 1s , VPAC 1 and VPAC 2 receptors were examined in transfected Cos7 cells for cAMP, IP 1 , pAkt, pERK and pCREB. Biased signalling was then quantified. The ability of antagonists to block PACAP‐38, PACAP‐27 or VIP stimulated cAMP accumulation at PACAP‐responsive receptors was also determined. PACAP‐responsive receptors exhibited varied pharmacological profiles but activated signalling in a similar manner. The PAC 1n and PAC 1s receptors displayed distinct pharmacology. At the PAC 1s receptor, VIP and PHM were more potent than at the PAC 1n receptor. PACAP‐responsive receptors displayed agonist‐dependent antagonism where PACAP‐38 was less effectively antagonised compared to PACAP‐27 and VIP. The distinct pharmacological profile displayed by the PAC 1s receptor suggests that it can act as a dual receptor for VIP and PACAP. Furthermore, the effectiveness of blocking a signalling pathway can be influenced by which endogenous PACAP family agonist is present. These effects have potential implications for the development and effectiveness of drugs targeting the PACAP system. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit oi/10.1111/bph.v179.3/issuetoc
Publisher: Wiley
Date: 14-02-2018
Abstract: The first synthesis of the anti-TB cyclic peptide callyaerin A (1), containing a rare (Z)-2,3-diaminoacrylamide bridging motif, is reported. Fmoc-formylglycine-diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1. Intramolecular cyclization between the formylglycine residue and the N-terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1. Synthetic 1 possessed potent anti-TB activity (MIC
Publisher: Wiley
Date: 25-08-2014
Publisher: Wiley
Date: 18-03-2011
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.EJMECH.2014.09.063
Abstract: 9-Deoxy analogues of the HRV 3C protease inhibitor (-)-thysanone display better inhibitory properties than the natural product, inferring the C9-OH hinders binding to the enzyme.
Publisher: Georg Thieme Verlag KG
Date: 02-07-2008
Publisher: Wiley
Date: 04-09-2012
Abstract: First described in the late 1960s, N-alkylsulfonylimines are heterocumulenes that participate in reactions with a range of 1,3-dipoles to afford interesting 3-, 4-, 5-, and 6-membered heterocycles. The distribution of adducts obtained suggests that multistage, stepwise mechanistic pathways rather than a concerted process are in operation.
Publisher: American Chemical Society (ACS)
Date: 26-02-2018
Abstract: The asymmetric total synthesis of the polyketide benzannulated spiroketal natural product, (-)-peniphenone A, is reported. The key reaction in the synthesis involved sp
Publisher: American Chemical Society (ACS)
Date: 05-08-2021
DOI: 10.1021/ACS.JNATPROD.1C00502
Abstract: The first total synthesis of the benzannulated 5,5-spiroketal natural products paeciloketal B and 1-
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C1OB05595J
Abstract: The enantioselective syntheses of deoxydihydrokalafungin (5), cis-deoxydihydrokalafungin (6) and deoxykalafungin (7) are reported. The strategy was based on 4 key reactions: (1) CBS reduction of prochiral ketone 10 to introduce chirality at C-1, (2) radical allylation of quinone 9a, (3) cross-metathesis of dimethoxynaphthalene 13 with methyl acrylate, and (4) intramolecular oxa-Michael addition of alcohol 8 to form the core naphthopyran ring system. This novel approach delivers naphthopyrans possessing the natural trans-stereochemistry observed in the pyranonaphthoquinone family of antibiotics.
Publisher: Elsevier BV
Date: 06-2005
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4OB01208A
Abstract: The synthesis of a library of N -glycosylated pramlintide analogues to establish the SAR of amylin receptor agonism has been undertaken.
Publisher: Wiley
Date: 28-10-2013
Publisher: American Chemical Society (ACS)
Date: 05-02-2015
DOI: 10.1021/JO502748S
Abstract: A robust synthetic approach to cis-γ-hydroxycarvone derivatives has been developed, enabling efficient access to synthetic building blocks for the growing family of bioactive sesterterpenoid natural products. Using this approach, an allyl bromide carvone derivative was used as the key building block for the total synthesis of the natural product phorbin A. This synthetic sequence also demonstrates the utility of benozyl enol ethers as an effective means of masking a β-ketophosphonate and their subsequent application in a one-pot benzoyl transfer-intramolecular Horner-Wadsworth-Emmons reaction.
Publisher: Wiley
Date: 20-07-2011
Publisher: Elsevier BV
Date: 12-2001
Publisher: Georg Thieme Verlag KG
Date: 25-09-2008
Publisher: International Union of Crystallography (IUCr)
Date: 22-10-2008
Publisher: Elsevier BV
Date: 06-2021
Publisher: Elsevier BV
Date: 09-2015
Publisher: Wiley
Date: 2010
DOI: 10.1002/BIP.21351
Abstract: During the course of developing a synthetic route for the cancer protein NY-ESO-1 using native chemical ligation, a number of the required thioester polypeptide fragments were unable to be synthesized effectively using Boc solid phase peptide synthesis. Modification of the SPPS protocols to include an arginine tag at the C terminus linked via the thioester resulted in a better purity profile and enhanced solubility, facilitating purification by HPLC. During preparation of another reactive partner for ligation that contained an internal Cys(Acm) residue by Fmoc SPPS, extensive loss of the Acm group occurred during cleavage from the resin while substitution with Cys(tBu) resulted in no loss of protecting group. It was shown that native chemical ligation of N-terminal cysteine peptide 155-180 containing the Cys(tBu) residue with thioester 140-154 was slow, incomplete and led to extensive HPLC column fouling. Subsequent incorporation of a C-terminal arginine tag into the N-terminal NY-ESO-1 155-180 fragment joined by a base labile 4-hydroxymethylbenzoic acid (HMBA) linker facilitated rapid quantitative ligation. The HMBA linker was demonstrated to be stable to the conditions required for native chemical ligation, subsequent transformations and final purification. Importantly it was effectively removed at pH=10.
Publisher: Royal Society of Chemistry (RSC)
Date: 2003
DOI: 10.1039/B303070A
Abstract: Homocoupling of naphthyl triflates 27, 16, 17 to the respective binaphthyls 28, 31 and 35 has been achieved in a one-pot procedure using bis(pinacolato)diboron and PdCl2(dppf). Use of potassium acetate as the base provides access to the initial naphthylboronate intermediates whereas the stronger base potassium phosphate is required in order to promote subsequent coupling of the naphthylboronate with a second equivalent of the naphthyl triflate. Attempts to convert binaphthyl 35 into bis-acetylnaphthalene 14, a key intermediate for the synthesis of the dimeric pyranonaphthoquinone antibiotic crisamicin A 2, via double Fries rearrangement of bis-acetate 37 derived from binaphthyl 35, were unsuccessful. Attempts to introduce the acetyl groups at C-7 and C-7' on bis-acetylnaphthalene 14 via Fries rearrangement of the monomeric precursors 21 and 15, before effecting homocoupling to a biaryl were unsuccessful. Introduction of an acetyl group via initial bromination ortho to the hydroxyl group in naphthol 18, which bears an electron rich benzyl ether at C-7, was plagued by the formation of phenolic coupling product 42 and naphthoquinone 43. Bromination of naphthol 45, bearing a less electron rich triflate group at C-7, also afforded binaphthol 47 resulting from phenolic coupling as well as naphthoquinone 48 when using N-bromosuccinimide at low temperature.
Publisher: Elsevier BV
Date: 08-2012
Publisher: Elsevier BV
Date: 1990
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B911514P
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC00952A
Abstract: Convergent chemo-enzymatic synthesis of mannosylated glycopeptides enhances uptake by human antigen presenting cells whilst preserving the immunogenicity of peptide epitopes.
Publisher: Wiley
Date: 12-12-2007
Publisher: Georg Thieme Verlag KG
Date: 09-2008
Publisher: Wiley
Date: 03-2014
DOI: 10.1002/BIP.22445
Abstract: ORFV002 is a novel orf viral protein (117 Aa) that inhibits nuclear events through the regulation of the transcriptional activity of NF‐κB, a master regulator of human gene expression (Diel et al., J Virol 2011, 85, 264–275). It is identified as the first nuclear inhibitor of NF‐κB produced by orf virus (ORFV) and no homologues in other genera of the Chordopoxvirinae subfamily have been reported to date (Diel et al., J Virol 2011, 85, 264–275). Our molecular structure predictions suggest that ORFV002 may mimic part of IκB, an inhibitor and natural human partner of NF‐κB. Recent advances in total chemical synthesis of proteins have provided solutions in overcoming challenges of current recombinant methods of protein isolation for structure elucidation. Aided by Boc solid phase peptide synthesis and native chemical ligation, ORFV002 was successfully synthesized in multimilligram amounts in good yield and high purity. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 137–144, 2014.
Publisher: American Chemical Society (ACS)
Date: 22-03-2021
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6CC10146A
Abstract: The first use of MALDI-imaging, as a snapshot tool to characterize multicomponent self-assembling peptide fibers.
Publisher: International Union of Crystallography (IUCr)
Date: 29-03-2008
Publisher: Springer New York
Date: 2009
Publisher: American Chemical Society (ACS)
Date: 22-09-2011
DOI: 10.1021/OL202333U
Abstract: Click phosphorylation of a propargylated unprotected peptide and phosphoryl azide using chaotrope-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition enabled a high-yielding and rapid synthesis of a nucleoside diphosphate kinase (NDPK) phosphocarrier domain. The synthesis showcases a valuable synthetic platform for the synthesis of biologically relevant phosphopeptide analogues.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0RA03011B
Abstract: Self-assembling peptide H4LMAX-RGDS hydrogels, designed to enhance bone regeneration, are cytocompatible and capable of delivering the bone anabolic factor lactoferrin to increase osteoblast cell number.
Publisher: Georg Thieme Verlag KG
Date: 06-03-2013
Publisher: Springer Science and Business Media LLC
Date: 09-03-2010
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4OB02536A
Abstract: The strong interaction between advanced glycation end-products and Cu( ii ) ions has been revealed using site-specifically glycated collagenous peptides.
Publisher: Elsevier BV
Date: 03-1998
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4NP00153B
Abstract: The rubromycins are a unique family of natural products. This review covers their isolation, biological activity, biosynthesis and a detailed discussion of the erse chemistry employed for total synthesis.
Publisher: Elsevier BV
Date: 02-2002
Publisher: Elsevier BV
Date: 07-1998
Publisher: American Chemical Society (ACS)
Date: 21-10-2003
DOI: 10.1021/OL035723C
Abstract: [reaction: see text] The synthesis of the fused aromatic spiroketal core of gamma-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.
Publisher: Wiley
Date: 03-09-2020
Publisher: MDPI AG
Date: 02-06-2018
DOI: 10.3390/NU10060714
Publisher: American Chemical Society (ACS)
Date: 22-11-2019
Abstract: The first syntheses of the cytotoxic peptides lipovelutibols B and D are described. While lipovelutibol D was prepared using solid-phase peptide synthesis followed by an
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3RA42781A
Publisher: Georg Thieme Verlag KG
Date: 13-02-2020
Abstract: Cyclic imine marine toxins have attracted considerable attention from the synthetic community in the past two decades due to their unique chemical structures and clinically relevant biological activities. This review presents recent efforts of our group in the development of various strategies to efficiently construct the common spirocyclic imine fragments of the cyclic imine toxins. In particular, the use of α,β-unsaturated N-acyl iminium ion dienophiles in Diels–Alder reactions are highlighted, whereby direct access to spirocyclic imine motifs was obtained and important mechanistic details were discovered. Alternative approaches to spirocyclic imine systems involving hydroamination of amino alkynes are also summarized. One such approach led to serendipitous access to N-vinyl amide products, while our most recently reported approach involving an intermolecular Diels–Alder/cross-coupling sequence using novel 2-bromo-1,3-butadienes to access 5,6-spirocyclic imines is also discussed. Additionally, the development of a novel method to construct another challenging motif present in the portimines is also introduced. 1 Introduction 2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine Toxins 2.1 Diels–Alder Cycloadditions of α,β-Unsaturated N-Acyl Iminium Dienophiles 2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles 2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reactions 2.4 Other Notable Strategies towards Spirocyclic Imines 2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin Portimine A 2.6 Construction of Another Challenging Motif of Portimine A 3 Conclusion and Future Perspectives
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3CB00075C
Abstract: Viral infections are one of the leading causes of acute morbidity in humans and much endeavour has been made by the synthetic community for the development of drugs to treat associated diseases.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CC07532K
Abstract: The heronapyrroles are a family of antibiotic natural products containing the rare 2-nitropyrrole motif.
Publisher: Wiley
Date: 23-05-2017
Abstract: The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and α,β-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+2] azide-enolate cycloaddition involving a vinyl azide generated in situ. A survey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis. Intriguingly, this study suggests that (cautious) reevaluation of azidoethene as a synthetic reagent may be warranted.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.NEUROPHARM.2007.08.010
Abstract: The current study describes the neuroprotective effects of an endogenous diketopiperazine, cyclo-glycyl-proline (cyclic GP), in rats with hypoxic-ischemic brain injury and the pre-clinical development of an analogue, cyclo-L-glycyl-L-2-allylproline (NNZ 2591), modified for improved bioavailability. The compounds were given either intracerebroventricularly or subcutaneously 2h after hypoxia-ischemia. Histology, immunohistochemistry and behavior were used to evaluate treatment effects. The central uptake of NNZ 2591 was also examined in normal and hypoxic-ischemic injured rats by HPLC-mass spectrometry. Central administration of cyclic GP or NNZ 2591 reduced the extent of brain damage in the lateral cortex, the hippoc us and the striatum (p<0.001), with NNZ 2591 being more potent. NNZ 2591 was stable in the plasma and crossed the blood-brain barrier independent of hypoxic-ischemic injury. The level of NNZ 2591 in the CSF was maintained for 2 h after a single subcutaneous dose, and modest neuroprotection was seen after a bolus subcutaneous administration (overall p<0.001). Treatment with NNZ 2591 for 5 d subcutaneously improved somatosensory-motor function (p<0.05) and long-term histological outcome (overall p<0.0001). NNZ 2591 treatment not only reduced both caspase-3 mediated apoptosis and microglial activation but also enhanced astrocytic reactivity, which may mediate its protective effect. The pharmacokinetic profile and potent long-term protective effects of NNZ 2591 suggests its utility for the treatment of ischemic brain injury and other neurological conditions requiring chronic intervention.
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3OB00956D
Abstract: An assisted tandem Chan–Lam/CuAAC reaction was developed for the rapid assembly of triazole analogues.
Publisher: Georg Thieme Verlag KG
Date: 07-12-2010
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.ETAP.2008.09.007
Abstract: Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and LC/MS identification revealed that NRB undergoes metabolism primarily to hydroxylated form that was tentatively identified in both rat and non-rat species with NADPH as the preferred cofactor. However, the metabolic profile and the rate are different between species. Gender differences are also reported in the metabolic rate in rats and we postulate that this may be responsible for different toxic sensitivities seen between sexes. Using this knowledge, we aim to develop pharmacological tool(s) for use in designing a new class of drugs that can be targeted in a tissue-selective manner. Further in vivo pharmacokinetic with receptor affinity studies are warranted.
Publisher: Wiley
Date: 18-12-2013
DOI: 10.1002/PSC.2595
Abstract: A considerable quantity of an alkylation by-product is observed when using 3,6-dioxa-1,8-octanedithiol as a scavenger during acidic release of peptides containing the thioether amino acid methionine from the solid support. Adjustment of the cleavage conditions by replacement of 3,6-dioxa-1,8-octanedithiol with ethane dithiol or by using methionine sulfoxide as an alternative to methionine resulted in no such impurity. The by-product was detectable by liquid chromatography and mass spectrometry and characterised by NMR spectroscopy of an isolated model peptide. It could be effectively removed in a separate post cleavage step by treatment with dilute aqueous acid at 37 °C.
Publisher: American Chemical Society (ACS)
Date: 27-09-2012
DOI: 10.1021/OL302498V
Abstract: A highly convergent total synthesis of 7',8'-dihydroaigialospirol is described. Key steps of the synthesis include a Nozaki-Hiyama-Kishi (NHK) coupling of an iodoalkyne with an advanced phthalide-aldehyde and a remarkable one-pot acid-mediated global deprotection/spiroacetalization.
Publisher: American Chemical Society (ACS)
Date: 18-12-2013
DOI: 10.1021/OL403246J
Abstract: A flexible total synthesis of the 2-nitropyrrole-derived marine natural product, (+)-heronapyrrole C, is reported. The approach is based on regioselective access to key building blocks containing the rare 4-substituted 2-nitropyrrole motif. Sharpless asymmetric epoxidation and dihydroxylation and a Shi epoxidation were used to introduce the five stereogenic centers of the bis-THF-diol side chain. The N-benzoyloxymethyl (Boz) protecting group was crucial for functionalization of the 2-nitropyrrole moiety and enabling final deprotection under mild conditions.
Publisher: Elsevier BV
Date: 1990
Publisher: International Union of Crystallography (IUCr)
Date: 30-07-2005
Publisher: Elsevier BV
Date: 2012
Publisher: Walter de Gruyter GmbH
Date: 2007
Abstract: The synthesis of the ABC spiroacetal-containing fragment of the marine biotoxins, the pectenotoxins (PTXs), is described. The synthetic strategy involves appendage of the highly substituted tetrahydofuran C ring to the AB spiroacetal unit via stereocontrolled cyclization of a γ-hydroxyepoxide. The bis-spiroacetal moiety of the spirolide family of shellfish toxins is also described, making use of an iterative radical oxidative cyclization strategy.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Royal Society of Chemistry (RSC)
Date: 2007
DOI: 10.1039/B708265G
Abstract: The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2"R, 5"R, 7"R) after initial synthesis of the unnatural (2"S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2"R, 5"S, 7"S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2"S, 5"R, 7"R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2"S, 5"S, 7"S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4OB01325E
Abstract: This perspective updates recent developments (since 2012) in the synthesis of spiroketals using transition metal catalysis.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Springer Science and Business Media LLC
Date: 05-09-2012
Publisher: Georg Thieme Verlag KG
Date: 16-03-2012
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5CC03052H
Abstract: Pyrraline and a novel pyrraline-derived cross-link have been incorporated into collagenous peptides via Maillard condensations performed on resin-bound peptide sequences.
Publisher: Wiley
Date: 25-03-2020
DOI: 10.1002/JLCR.3838
Publisher: American Chemical Society (ACS)
Date: 07-02-2018
DOI: 10.1021/ACS.BIOCHEM.7B01180
Abstract: The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands. These two domains are joined together by a stretch of amino acids that is referred to as the "stalk". Studies of other class B GPCRs suggest that the stalk may act as hinge, allowing the ECD to adopt multiple conformations. It is unclear what the role of the stalk is within CLR and whether RAMPs can influence its function. Therefore, this study investigated the role of this region using an alanine scan. Effects of mutations were measured with all three RAMPs through cell surface expression, cAMP production and, in select cases, radioligand binding and total cell expression assays. Most mutants did not affect expression or cAMP signaling. CLR C127A, N140A, F142A, and L144A impaired cell surface expression with all three RAMPs. T125A decreased the potency of all peptides at all receptors. N128A, V135A, and L139A showed ligand-dependent effects. While the stalk appears to play a role in CLR function, the effect of RAMPs on this region seems limited, in contrast to their effects on the structure of CLR in other receptor regions.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3OB41066H
Abstract: A recently identified Antarctic fish protein termed antifreeze potentiating protein (AFPP) is thought to act as an adjunct to the previously characterised antifreeze glycoproteins (AFGPs), the two acting together to inhibit ice crystal growth in vivo. Elucidating the functional properties of the new AFPP requires access to large amounts of pure product, but the paucity of natural material necessitates alternative approaches. We therefore embarked on the total chemical synthesis of the AFPP, through a convergent ligation strategy. After many challenges, mostly due to the solubility issues of the peptide fragments, and several revisions of the original synthetic strategy, we have successfully synthesized a masked analogue of AFPP. The key to the successful synthesis was the use of a solubilising tag attached through a hydrolysable linker.
Publisher: MDPI AG
Date: 14-09-2020
DOI: 10.3390/MOLECULES25184214
Abstract: Dental caries or tooth decay is a preventable and multifactorial disease that affects billions of people globally and is a particular concern in younger populations. This decay arises from acid demineralisation of tooth enamel resulting in mineral loss from the subsurface. The remineralisation of early enamel carious lesions could prevent the cavitation of teeth. The enamel protein amelogenin constitutes 90% of the total enamel matrix protein in teeth and plays a key role in the biomineralisation of tooth enamel. The physiological importance of amelogenin has led to the investigation of the possible development of amelogenin-derived biomimetics against dental caries. We herein review the literature on amelogenin, its primary and secondary structure, comparison to related species, and its’ in vivo processing to bioactive peptide fragments. The key structural motifs of amelogenin that enable enamel remineralisation are discussed. The presence of several motifs in the amelogenin structure (such as polyproline, N- and C-terminal domains and C-terminal orientation) were shown to play a critical role in the formation of particle shape during remineralization. Understanding the function/structure relationships of amelogenin can aid in the rational design of synthetic polypeptides for biomineralisation, halting enamel loss and leading to improved therapies for tooth decay.
Publisher: Wiley
Date: 06-02-2013
Publisher: Bentham Science Publishers Ltd.
Date: 09-2003
Publisher: Wiley
Date: 07-11-2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00880H
Abstract: This review provides an account of the reported methods used for the synthesis of cyclotetrapeptides.
Publisher: Elsevier BV
Date: 05-1997
Publisher: Elsevier BV
Date: 06-2006
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.BMC.2012.07.010
Abstract: The α4β7 integrin is a well-known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes and multiple sclerosis. The synthesis of a small library of cell-permeable β7 integrin inhibitors based on the peptide biotin-R(8)ERY is reported, in which the tyrosine residue has been modified by using the Suzuki-Miyaura cross-coupling reaction. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn(2+)-activated adhesion of mouse TK-1 T cells to mouse MAdCAM-1. All of the synthesised peptidomimetics are more active than our previously reported lead compound biotin-R(8)ERY with two of the analogues, 6 and 7, exhibiting IC(50) values of <15 μM.
Publisher: Wiley
Date: 08-01-2014
Publisher: Wiley
Date: 22-08-2018
Abstract: The Diels-Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products however, successful application of the intermolecular Diels-Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels-Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB02929F
Abstract: The amyloidogenic Aβ42 peptide was efficiently prepared using a double linker system, markedly improving solubility and chromatographic peak resolution, thus enabling full characterisation using standard techniques. The tag was readily cleaved with sodium hydroxide and removed by aqueous extraction, affording Aβ42 in high purity and yield for biophysical characterisation studies.
Publisher: American Chemical Society (ACS)
Date: 27-01-2010
DOI: 10.1021/OL1001208
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.BMC.2012.08.053
Abstract: When administered in vivo, amylin (1-8) stimulates osteoblast proliferation increasing bone volume and bone strength. The native cyclic octapeptide amylin (1-8) is unstable, however, it provides an attractive framework for the creation of more stable, orally active synthetic analogues using various peptidomimetic techniques. On-resin ring closing metathesis (RCM) on the olefinic side chains of allylglycine residues and lysine moieties functionalized with an allyloxycarbonyl (Alloc) group, was used to prepare novel carba-bridged surrogates of the disulfide bridge between Cys/2 and Cys/7 in amylin-(1-8). Commercially available N(α)-Fmoc N(ε)-Alloc protected lysine was used as a convenient substrate for Grubbs' ring closing metathesis. Analogues of amylin-(1-8) prepared by cyclization of allylglycine residues that also contained proline residues at either position 4 or 6, or both, were also prepared to investigate the effect of proline as a 'kink-inducing' residue on the efficiency of the RCM reaction. Of the nine novel alkene-bridged analogues prepared, five showed promising biological activity in a proliferation study in primary foetal rat osteoblasts at physiological concentrations. Two of these analogues were chosen for further in vivo evaluation.
Publisher: American Chemical Society (ACS)
Date: 16-08-2019
Abstract: The integrastatins, epicoccolide A and epicoccongirone A, are natural products containing a unique [6.6.6.6]-tetracyclic core framework that exhibit a broad spectrum of biological activities. A synthesis of the common core of epicoccolide A and epicocconigrone A has been achieved using an umpolung alkylation-lactonization to assemble an isochromanone from which the bridged 1,3-dioxane was readily assembled. A different strategy was required to access the core on the integrastatins an initial aryllithium addition to an aldehyde, followed by oxidation and treatment of the masked dihydroxyketone with acid gave the desired core structure.
Publisher: Royal Society of Chemistry (RSC)
Date: 2009
DOI: 10.1039/B818314G
Abstract: The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids were generated via nucleosidation of acetoxy-spiroacetal with a series of silylated nucleobases under Vorbrüggen conditions.
Publisher: International Union of Crystallography (IUCr)
Date: 24-05-2008
Publisher: American Chemical Society (ACS)
Date: 26-10-2010
DOI: 10.1021/CG1005083
Publisher: Royal Society of Chemistry (RSC)
Date: 2004
DOI: 10.1039/B401119H
Abstract: The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.
Publisher: Wiley
Date: 10-07-2019
Abstract: Syn dihydroxyketone motifs are embedded in a wide range of biologically active natural products, however the development of stereoselective synthetic methods to assemble these structures has proven a challenging task. We report a highly diastereoselective method for the synthesis of syn dihydroxyketones from propargylic alcohols, with wide scope for application in natural product synthesis. The reaction sequence involves regioselective cyclisation of propargylic alcohols with incorporation of a triketone to give enol dioxolanes that are then diastereoselectively epoxidised to form unusual spiroepoxide intermediates. Hydrolysis affords syn dihydroxyketones as essentially single diastereisomers. The reaction sequence is operationally simple, of wide substrate scope, and remarkably can be efficiently carried out as a one‐pot process with no loss of overall yield or diastereoselectivity.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3OB41065J
Abstract: This article describes our efforts to develop an asymmetric synthesis of bisbenzannulated spiroketals using a chiral sulfoxide auxiliary. Our primary focus was on the synthesis of the 3H-spiro[benzofuran-2,2'-chroman] ring system, the spirocyclic core of the rubromycin family. Our strategy employed the use of lithium-halogen exchange on a racemic bromospiroketal in order to attach a chiral sulfoxide, thus producing two diastereomers. The diastereomers were separable, enabling isolation of each spiroketal enantiomer. Subsequent cleavage of the sulfoxide group from each diastereomer yielded the respective parent spiroketal in high enantiopurity.
Publisher: Hindawi Limited
Date: 09-01-2019
DOI: 10.1002/ER.4347
Publisher: Wiley
Date: 23-12-2013
DOI: 10.1111/BPH.12464
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0NP00052C
Abstract: This highlight reviews the efficient synthesis of trans -bicyclo[4.4.0]decane/decene-containing natural products, providing handles for selectively constructing next generation therapeutics for a post-antibiotic era.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2013
DOI: 10.1007/S00726-013-1498-9
Abstract: Advanced Glycation Endproducts (AGEs) are modified amino acids that form on proteins and are known to be implicated in the pathogenesis of diabetes and related diseases. Ready access to synthetic stable isotope-labelled AGEs allows for quantitative mass spectrometry studies to be undertaken, providing key insights into the roles AGEs play in the progression of such diseases. However, the majority of current syntheses of these compounds suffer from poor yields and lengthy procedures and are not suitable for the purposes required here. Here, we report robust syntheses of stable isotope-labelled monolysyl AGEs, N(ε)-(carboxymethyl)lysine, N(ε)-(carboxyethyl)lysine and pyrraline, that provide straightforward access to these compounds for quantitative amino acid analysis. This work will facilitate future investigations with these compounds and lead to a better understanding of the roles they play in diabetes and related diseases.
Publisher: American Chemical Society (ACS)
Date: 05-04-2022
Publisher: Wiley
Date: 04-05-2016
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.LFS.2014.03.020
Abstract: Diabetes elicits cardiac metabolic stress involving impaired glucose uptake and metabolic substrate shifts. Diabetic cardiac pathology is well documented in human patients and experimental animal models to be characterized by diastolic dysfunction, but the underlying mechanisms are not well understood. Signaling disturbances involved in cardiac insulin resistance are linked to glucose handling abnormalities. Both reversible (e.g. O-GlcNAc) and irreversible (e.g. AGEs) glucose-modifications of cardiomyocyte extracellular and intracellular proteins are implicated in structural and functional alterations underlying pathology in the diabetic heart. This review highlights some aspects of the epigenetic roles played by glucose (and related hexose sugars) in mediating diabetic cardiac pathology with specific consideration for the mechanisms impinging on post-translational modifications which have key signaling and mechanical impacts.
Publisher: Wiley
Date: 23-08-2017
Publisher: American Chemical Society (ACS)
Date: 27-09-2010
DOI: 10.1021/JO1016585
Abstract: A microwave-assisted chemoenzymatic resolution has been used to install the C3 stereocenter of the reported structure of the fungal metabolite herbaric acid in high enantiomeric excess. The synthesis and stereochemical assignment was accomplished using a completely regioselective anti-Markovnikov addition of water to vinylphthalide 3, achieved using a heteroatom-directed Wacker oxidation that proceeds with retention of stereochemistry. These results establish that so-called "reverse" Wacker oxidations are a viable alternative to hydroboration/oxidation procedures.
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8OB01230J
Abstract: The proposed structure of talarolide A, a cycloheptapeptide featuring a hydroxamate moiety within the peptide backbone, was successfully synthesized.
Publisher: American Chemical Society (ACS)
Date: 02-08-2021
DOI: 10.1021/ACS.JNATPROD.1C00222
Abstract: Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from
Publisher: MDPI AG
Date: 23-06-2022
DOI: 10.3390/DAIRY3030032
Abstract: The drug-likeness and pharmacokinetic properties of 23 dairy-protein-derived opioid peptides were studied using SwissADME and ADMETlab in silico tools. All the opioid peptides had poor drug-like properties based on violations of Lipinski’s rule-of-five. Moreover, prediction of their pharmacokinetic properties showed that the peptides had poor intestinal absorption and bioavailability. Following this, two well-known opioid peptides (βb-casomorphin-5, βb-casomorphin-7) from A1 bovine milk and caffeine (positive control) were selected for in silico molecular docking and in vitro inhibition study with two cholinesterase enzyme receptors important for the pathogenesis of Alzheimer’s disease. Both peptides showed higher binding free energies and inhibitory activities to butyrylcholinesterase (BChE) than caffeine, but in vitro binding energy values were lower than those from the docking model. Moreover, the two casomorphins had lower inhibitory properties against acetylcholinesterase (AChE) than caffeine, although the docking model predicted the opposite. At 1 mg/mL concentrations, βb-casomorphin-5 and βb-casomorphin-7 showed promising results in inhibiting both cholinesterases (i.e., respectively 34% and 43% inhibition of AChE, and 67% and 81% inhibition of BChE). These dairy-derived opioid peptides have the potential to treat Alzheimer’s disease via cholinesterase inhibition. However, appropriate derivatization may be required to improve their poor predicted intestinal absorption and bioavailability.
Publisher: Wiley
Date: 25-07-2006
DOI: 10.1002/MRC.1878
Abstract: The 1H and 13C NMR spectra of 3-azabicyclo[3.3.1]nonanes with various oxygenated substituents at C-6 were assigned using 1D (DEPT) and 2D (COSY, HSQC, HMBC, NOESY) experiments. Close examination of this NMR data details the effects of substitution and stereochemistry at C-6 in these compounds.
Publisher: Elsevier BV
Date: 2007
Publisher: Elsevier BV
Date: 05-2019
Publisher: Georg Thieme Verlag KG
Date: 06-2006
Publisher: Elsevier BV
Date: 07-2012
Publisher: Wiley
Date: 19-02-2013
Abstract: Spiropins for SPPS: The rigid structure of an anomerically stabilised spiroketal motif enables the appendage of substituents in a fixed conformation. To assess the ability of a spiroketal motif to induce a turn structure and participate in solid-phase peptide synthesis (SPPS), an Fmoc-spiroketal amino acid was synthesised and incorporated into a spiroketal-containing cyclic peptide.
Publisher: American Chemical Society (ACS)
Date: 10-2018
Abstract: Fundamental study of the reactivity of 2-nitropyrrole systems has enabled the identification of effective methods for incorporation of this unusual motif into advanced natural product frameworks. The presence of electron-rich pyrrole N-protecting groups (BOM, Boz) was demonstrated to enable a variety of previously unsuccessful palladium-mediated cross-couplings to be carried out in high yield. Based on this foundation, a series of regio- and stereoselective synthetic routes toward the nitropyrrolin and heronapyrrole families of natural products was developed by our group (G1-3). A full account of the strategic evolution of these approaches is reported here, highlighting the details of the setbacks encountered and eventual successes achieved en route, including the total synthesis of heronapyrrole B. The fundamental studies and completed total syntheses provide general access to the bioactive 2-nitropyrrole natural product manifold and also establish practical and efficient methods for preparation and elaboration of the medicinally relevant 2-nitropyrrole motif.
Publisher: Wiley
Date: 08-1992
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1NP00043H
Abstract: A review discussing the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with discussion of their total synthesis and biosynthesis.
Publisher: American Chemical Society (ACS)
Date: 09-10-2012
DOI: 10.1021/OL3025956
Abstract: The total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring closing metathesis/olefin isomerization reaction. The synthetic work described herein serves to confirm the recent structural revision of this unusual natural product.
Publisher: American Chemical Society (ACS)
Date: 14-01-2009
DOI: 10.1021/OL8029017
Abstract: The synthesis of enantiopure bicyclic alpha,alpha-disubstituted spirolactams is described using a diastereoselective Birch reductive alkylation as the key step. Hydrogenation of the resultant alkylated cyclohexadienes followed by intramolecular cyclization provides access to enantiopure 8-azaspiro[5.6]dodecan-7-ones.
Publisher: Wiley
Date: 12-04-2013
DOI: 10.1111/BPH.12118
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9OB01598A
Abstract: A review discussing the isolation, biological activity, biosynthesis, and total synthesis of naturally occurring benzannulated spiroketals.
Publisher: Informa Healthcare
Date: 05-02-2015
DOI: 10.1517/14728222.2015.1010514
Abstract: Exogenous IGF-1 protects the brain from ischemic injury and improves function. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. In this review, the authors have discussed the efficacy, pharmacokinetics and mechanisms of IGF-1 derivatives on protecting acute brain injury, preventing memory impairment and improving recovery from neurological degenerative conditions evaluated in various animal models. We have included natural metabolites of IGF-1, glycine-proline-glutamate (GPE), cleaved from N-terminal IGF-1 and cyclic glycine-proline (cGP) as well as the structural analogues of GPE and cGP, glycine-2-methyl-proline-glutamate and cyclo-l-glycyl-l-2-allylproline, respectively. In addition, the regulatory role for cGP in bioavailability of IGF-1 has also been discussed. These small neuropeptides provide effective neuroprotection by offering an improved pharmacokinetic profile and more practical route of administration compared with IGF-1 administration. Developing modified neuropeptides to overcome the limitations of their endogenous counterparts represents a novel strategy of pharmaceutical discovery for neurological disorders. The mechanism of action may involve a regulation of IGF-1 bioavailability.
Publisher: Wiley
Date: 15-10-2021
DOI: 10.1111/BPH.15628
Abstract: The calcitonin (CT) receptor family is complex, comprising two receptors (the CT receptor [CTR] and the CTR‐like receptor [CLR]), three accessory proteins (RAMPs) and multiple endogenous peptides. This family contains several important drug targets, including CGRP, which is targeted by migraine therapeutics. The pharmacology of this receptor family is poorly characterised in species other than rats and humans. To facilitate understanding of translational and preclinical data, we need to know the receptor pharmacology of this family in mice. Plasmids encoding mouse CLR/CTR and RAMPs were transiently transfected into Cos‐7 cells. cAMP production was measured in response to agonists in the absence or presence of antagonists. We report the first synthesis and characterisation of mouse adrenomedullin, adrenomedullin 2 and βCGRP and of mouse CTR without or with mouse RAMPs. Receptors containing m‐CTR had subtly different pharmacology than human receptors they were promiscuous in their pharmacology, both with and without RAMPs. Several peptides, including mouse αCGRP and mouse adrenomedullin 2, were potent agonists of the m‐CTR:m‐RAMP3 complex. Pharmacological profiles of receptors comprising m‐CLR:m‐RAMPs were generally similar to those of their human counterparts, albeit with reduced specificity. Mouse receptor pharmacology differed from that in humans, with mouse receptors displaying reduced discrimination between ligands. This creates challenges for interpreting which receptor may underlie an effect in preclinical models and thus translation of findings from mice to humans. It also highlights the need for new ligands to differentiate between these complexes. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary).. To view the other articles in this section visit oi/10.1111/bph.v179.3/issuetoc
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/CH10464
Abstract: Antifreeze glycoproteins (AFGPs) are glycosylated polypeptides produced by Antarctic and Arctic fishes, which allow them to survive in seawater at sub-zero temperatures. An investigation into the postulated enteric uptake of AFGP synthesized in the exocrine pancreas of Antarctic fishes required a custom-prepared AFGP probe that incorporated seven isotopically-labelled Ala residues for detection by mass spectrometry. The AFGPs are composed of a repetitive three amino acid unit (Ala-Ala-Thr), in which the threonine residue is glycosylated with the disaccharide β-d-Gal-(1→3)-α-d-GalNAc. The synthesis of isotopically-labelled AFGP8 (1), as well as the optimized synthesis of the protected glycosylated amino acid building block 2, is reported.
Publisher: International Union of Crystallography (IUCr)
Date: 15-01-2001
DOI: 10.1107/S0108270100013950
Abstract: The crystal structure of antibiotic CP44,161, 6-(7-(2-ethyl-2-[5-(1-hydroxymethyl)-5-methyl-2,3,4,5-tetrahydro-2-furyl]-4,10,-12-trimethyl-1,6,8-trioxadispiro[4.1.5.3]pentadec-13-en-9-yl)-4-hydroxy-3,5-dimethyl-6-oxononyl)-2-hydroxy-3-methylbenzoic acid monohydrate, C43H66O10.H2O, has been determined by X-ray crystallography. The molecule adopts a cyclic conformation, with a centrally located water molecule contributing to the stability of the conformation through hydrogen-bonding interactions.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.BBAPAP.2013.04.031
Abstract: Nedd4-1 (neuronal precursor cell expressed developmentally downregulated gene 4-1) is an E3 ubiquitin ligase that interacts with and negatively regulates the epithelial Na(+) channel (ENaC). The WW domains of Nedd4-1 bind to the ENaC subunits via recognition of PY motifs. Human Nedd4-1 (hNedd4-1) contains four WW domains with the third domain (WW3*) showing the strongest affinity to the PY motif. To understand the mechanism underlying this binding affinity, we have carried out NMR structural and dynamics analyses of the hNedd4-1 WW3* domain in complex with a peptide comprising the C-terminal tail of the human ENaC α-subunit. The structure reveals that the peptide interacts in a similar manner to other WW domain-ENaC peptide structures. Crucial interactions that likely provide binding affinity are the broad XP groove facilitating additional contacts between the WW3* domain and the peptide, compared to similar complexes, and the large surface area buried (83Å(2)) between R430 (WW3*) and L647' (αENaC). This corroborates the model-free analysis of the (15)N backbone relaxation data, which showed that R430 is the most rigid residue in the domain (S(2)=0.90±0.01). Carr-Purcell-Meiboom-Gill relaxation dispersion analysis identified two different conformational exchange processes on the μs-ms time-scale. One of these processes involves residues located at the peptide binding interface, suggesting conformational exchange may play a role in peptide recognition. Thus, both structural and dynamic features of the complex appear to define the high binding affinity. The results should aid interpretation of biochemical data and modeling interfaces between Nedd4-1 and other interacting proteins.
Publisher: Wiley
Date: 14-09-2018
Abstract: Several hundred (396) compounds from New Zealand flora with medicinal properties were analyzed for their physicochemical properties. It was found that approximately 10 % fulfilled all the requirements to be considered to be lead-like, over half of the compounds were deemed to be in the drug-like space and ≈75 % were in the known drug space. These results indicate the presence of a significant proportion of compounds that are of particular interest to pursue as potential lead compounds or therapeutics. Additionally, compound classes were analyzed separately-most carbonyl-containing compounds (aldehydes, ketones, esters and lactones), along with phenols were the most lead-like compounds, which also displayed very good proportions in the drug-like and known drug space. The information presented herein can be harnessed and utilized in future work, through focussing on the compounds and compound classes that exhibit high-levels of lead-likeness for further development.
Publisher: Wiley
Date: 23-02-2018
Publisher: Georg Thieme Verlag KG
Date: 08-06-2009
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0OB00315H
Abstract: The synthesis of the antimicrobial cyclic peptide xenematide was accomplished by Fmoc solid phase peptide synthesis and the key esterification reaction was achieved using a modified Yamaguchi esterification. Comparison of the optical rotation and NMR data of the synthesized diastereomers to that of the natural product confirmed the structure of xenematide to be PA-L-[Thr-L-Trp-D-Trp-β-Ala]. (PA = phenylacetyl).
Publisher: MDPI AG
Date: 24-03-2021
DOI: 10.3390/MOLECULES26071819
Abstract: Phytophthora is a genus of microorganisms that cause devastating dieback and root-rot diseases in thousands of plant hosts worldwide. The economic impact of Phytophthora diseases on crops and native ecosystems is estimated to be billions of dollars per annum. These invasive pathogens are extremely difficult to control using existing chemical means, and the effectiveness of the few treatments available is being jeopardized by increasing rates of resistance. There is an urgent need to identify new chemical treatments that are effective against Phytophthora diseases. Natural products have long been regarded as “Nature’s medicine chest”, providing invaluable leads for developing front-line drugs and agrochemical agents. Here, we have screened a natural product-inspired library of 328 chemicals against two key Phytophthora species: Phytophthora cinnamomi and Phytophthora agathidicida. The library was initially screened for inhibition of zoospore germination. From these screens, we identified twenty-one hits that inhibited germination of one or both species. These hits were further tested in mycelial growth inhibition studies to determine their half-maximal inhibitory concentrations (IC50s). Four compounds had IC50 values of approximately 10 µM or less, and our best hit had IC50s of approximately 3 µM against both Phytophthora species tested. Overall, these hits may serve as promising leads for the development of new anti-Phytophthora agrochemicals
Publisher: American Chemical Society (ACS)
Date: 23-08-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2OB01864K
Abstract: Our study describes how regio- and stereochemistry influences the antifouling activity of naturally inspired 2,5-diketopiperazines.
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B813605J
Abstract: The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to the cardinalins is described. Whilst attempts to effect a double Hauser-Kraus annulation of enone 5 were unsuccessful using both bis-phthalide 4 and bis-sulfone 21, a single annulation of cyanophthalide 28 with enone 5 furnished functionalised naphthalene 31. Suzuki-Miyaura homocoupling of the aryl triflate 29 derived from 31 effected a late-stage construction of the biaryl bond and facilitated access to the biaryl 3. Double stereoselective lactol reduction installed the 1,3-cis stereochemistry of the pyran rings and a final double oxidative demethylation step furnished model dimer 1, completing the enantioselective synthesis of a dimeric pyranonaphthoquinone bearing the core structure of cardinalin 3.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.PEPTIDES.2019.04.011
Abstract: Pancreatic islet-derived peptide hormones play key roles in the maintenance of systemic energy homeostasis and glucose balance and defects in their regulation are strongly implicated in the pathogenesis of obesity and diabetes. Peptides have also been used as lead compounds for therapeutics targeting metabolic disease. It is therefore important to understand the activity and function of islet hormones in both their target tissues and the whole organism. Insulin-like growth factor II (IGF-II) is an insulin homolog secreted by the islet β-cells. Vesiculin is a newly discovered peptide hormone, processed from IGF-II and secreted from islet β-cells in response to glucose. We postulated that vesiculin might act to regulate systemic glucose metabolism. Here we report our original investigations of vesiculin's activity in relation to glucoregulation. Vesiculin and IGF-II displayed similar dose-response relationships for lowering blood glucose in insulin-responsive FVB/n mice. By contrast, the ability of IGF-II to lower blood glucose was blunted in insulin-resistant triprolyl human-amylin transgenic mice, whereas vesiculin's ability to lower blood glucose remained unaffected. We also confirmed the ability of vesiculin to bypass insulin resistance in a second mouse model. In vitro analysis of signalling by vesiculin and IGF-II indicates that, like IGF-II, vesiculin signals through the IR/ IGF1R. Overall, we show that removal of only four amino acids from IGF-II has generated a peptide hormone with different bioactivity relevant to blood-glucose regulation. Investigating the differences among vesiculin, IGF-II and insulin signalling and activity may provide new insights into insulin resistance and potentially inform the design of novel therapeutics.
Publisher: Georg Thieme Verlag KG
Date: 06-08-2014
Publisher: Wiley
Date: 11-02-2021
Publisher: Wiley
Date: 18-05-2011
Abstract: A novel route to simple 6,5‐benzannulated spiroketal analogues has been developed. A convergent Horner–Wadsworth–Emmons olefination enabled ready assembly of the spiroketal precursors. Use of a benzyl protecting group strategy enabled an efficient one‐pot hydrogenation/deprotection/spiroketalisation process to be employed providing a robust method to access a range of substituted aromatic monobenzannulated spiroketals.
Publisher: Wiley
Date: 25-11-2016
Publisher: American Chemical Society (ACS)
Date: 22-11-2022
DOI: 10.1021/ACSINFECDIS.1C00347
Abstract: With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS). We then designed and synthesized 38 polymyxin analogues, incorporating these unique building blocks at the N-terminus, or to replace hydrophobic residues at positions 6 and 7 of the native lipopeptides. Several polymyxin analogues bearing one or more S
Publisher: Georg Thieme Verlag KG
Date: 10-01-2014
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2013
End Date: 2016
Funder: Marsden Fund
View Funded ActivityStart Date: 2015
End Date: 2018
Funder: Marsden Fund
View Funded ActivityStart Date: 2004
End Date: 2006
Funder: James Cook Research Fellowship
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: Ministry of Business, Innovation and Employment
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Marsden Fund
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Marsden Fund
View Funded Activity