ORCID Profile
0000-0002-0767-5196
Current Organisation
University of Sydney
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Organic Chemical Synthesis | Biologically Active Molecules | Bioinorganic chemistry | Biologically active molecules | Organic Chemistry | Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Sensor Technology (Chemical aspects) | Bioinorganic Chemistry | Receptors and Membrane Biology | Inorganic chemistry | Structural Biology (incl. Macromolecular Modelling) | Biophysics | Enzymes | Mycology | Analytical Biochemistry | Analytical Biochemistry | Bioinformatics |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Rice | Cardiovascular system and diseases | Cancer and related disorders | Biological sciences | Infectious Diseases
Related Links
Publications
cis-Dihydroxylation of Alkenes by a Non-Heme Iron Enzyme Mimic
Publisher: Georg Thieme Verlag KG
Date: 08-2008
Efficient deprotection of F-BODIPY derivatives: Removal of BF2 using brønsted acids
Publisher: Beilstein Institut
Date: 09-01-2015
DOI: 10.3762/BJOC.11.6
Abstract: The effective and efficient removal of the BF 2 moiety from F -BODIPY derivatives has been achieved using two common Brønsted acids treatment with trifluoroacetic acid (TFA) or methanolic hydrogen chloride (HCl) followed by work-up with Ambersep ® 900 resin (hydroxide form) effects this conversion in near-quantitative yields. Compared to existing methods, these conditions are relatively mild and operationally simple, requiring only reaction at room temperature for six hours (TFA) or overnight (HCl).
Selective Displacement of a Scorpionand Triazole Ligand from Metallocyclam Complexes Visualised with NMR Spectroscopy
Publisher: Wiley
Date: 17-02-2017
Conglobatins B–E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin
Publisher: Springer Science and Business Media LLC
Date: 17-06-2020
Boronated phosphonium salts containing arylboronic acid, closo-carborane, or nido-carborane: Synthesis, X-ray diffraction, in vitro cytotoxicity, and cellular uptake
Publisher: Springer Science and Business Media LLC
Date: 06-08-2010
DOI: 10.1007/S00775-010-0690-6
Abstract: The preparation of boronated triaryl and tetraaryl phosphonium salts of the type [PPh(3)CH(2)R]Br [R is 4-boronophenyl (1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (2), 3-boronophenyl (3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (4), 2-boronophenyl (5), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (6), and closo-1,2-carboran-1-yl (7)] is described. These compounds were prepared by the reaction of triphenylphosphine with benzylic bromides or 1-bromomethyl-closo-1,2-carborane in acetonitrile solution at 85 °C. The zwitterionic nido-7,8-carborane derivative PPh(3)CH(2)C(2)B(9)H(11) (8) was prepared by treatment of 7 with cesium fluoride in refluxing ethanol. All compounds were fully characterized by multinuclear ((1)H, (11)B, (13)C, and (31)P) 1D- and 2D-NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis, and single-crystal X-ray structures were determined for compounds 1, 3, 7, and 8. The cytotoxicities and boron uptake of selected derivatives were investigated in vitro using human glioblastoma (T98G) and canine kidney tubule (MDCK II) cells. The zwitterionic species 8 was found to be the least cytotoxic agent while also delivering the greatest amount of boron to the T98G cells, peaking at 9.15 ± 2.65 μg B/mg protein.
Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials
Publisher: American Chemical Society (ACS)
Date: 06-05-2020
DOI: 10.26434/CHEMRXIV.12212927.V1
Abstract: We have discovered and studied a tele substitution reaction in a biologically important heterocyclic ring system. Conditions that favour the tele -substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the in vivo active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium. Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link ses.library.usyd.edu.au/handle/2123/21890 . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds.
Combined “dual” absorption and fluorescence smartphone spectrometers
Publisher: The Optical Society
Date: 08-04-2015
DOI: 10.1364/OL.40.001737
Isopenicillin N Synthase: Crystallographic Studies
Publisher: Wiley
Date: 25-03-2021
Abstract: Isopenicillin N synthase (IPNS) is a non-heme iron oxidase (NHIO) that catalyses the cyclisation of tripeptide δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to bicyclic isopenicillin N (IPN). Over the last 25 years, crystallography has shed considerable light on the mechanism of IPNS catalysis. The first crystal structure, for apo-IPNS with Mn bound in place of Fe at the active site, reported in 1995, was also the first structure for a member of the wider NHIO family. This was followed by the anaerobic enzyme-substrate complex IPNS-Fe-ACV (1997), this complex plus nitric oxide as a surrogate for co-substrate dioxygen (1997), and an enzyme product complex (1999). Since then, crystallography has been used to probe many aspects of the IPNS reaction mechanism, by crystallising the protein with a ersity of substrate analogues and triggering the oxidative reaction by using elevated oxygen pressures to force the gaseous co-substrate throughout protein crystals and maximise synchronicity of turnover in crystallo. In this way, X-ray structures have been elucidated for a range of complexes closely related to and/or directly derived from key intermediates in the catalytic cycle, thereby answering numerous mechanistic questions that had arisen from solution-phase experiments, and posing many new ones. The results of these crystallographic studies have, in turn, informed computational experiments that have brought further insight. These combined crystallographic and computational investigations augment and extend the results of earlier spectroscopic analyses and solution phase studies of IPNS turnover, to enrich our understanding of this important protein and the wider NHIO enzyme family.
Total synthesis of a novel 2-thiabicyclo[3.2.0]heptan-6-one analogue of penicillin N
Publisher: Elsevier BV
Date: 10-2003
Tele-Substitution Reactions in the Synthesis of a Promising Class of Antimalarials
Publisher: American Chemical Society (ACS)
Date: 06-05-2020
DOI: 10.26434/CHEMRXIV.12212927
Abstract: We have discovered and studied a i tele /i substitution reaction in a biologically important heterocyclic ring system. Conditions that favour the i tele /i -substitution pathway were identified: the use of increased equivalents of the nucleophile or decreased equivalents of base, or the use of softer nucleophiles, less polar solvents and larger halogens on the electrophile. Using results from X-ray crystallography and isotope labelling experiments a mechanism for this unusual transformation is proposed. We focused on this triazolopyrazine as it is the core structure of the i in vivo /i active anti-plasmodium compounds of Series 4 of the Open Source Malaria consortium. Archive of the electronic laboratory notebook with the description of all conducted experiments and raw NMR data could be accessed via following link a href="ses.library.usyd.edu.au/handle/2123/21890" ses.library.usyd.edu.au/handle/2123/21890 /a . For navigation between entries of laboratory notebook please use file "Strings for compounds in the article.pdf" that works as a reference between article codes and notebook codes, also this file contain SMILES for these compounds. br
Lab-in-a-Phone: Smartphone-Based Portable Fluorometer for pH Measurements of Environmental Water
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2015
The reaction cycle of isopenicillin N synthase observed by X-ray diffraction
Publisher: Springer Science and Business Media LLC
Date: 10-1999
DOI: 10.1038/44400
Abstract: Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the biosynthesis of isopenicillin N (IPN), the precursor of all penicillins and cephalosporins. The key steps in this reaction are the two iron-dioxygen-mediated ring closures of the tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV). It has been proposed that the four-membered beta-lactam ring forms initially, associated with a highly oxidized iron(iv)-oxo (ferryl) moiety, which subsequently mediates closure of the five-membered thiazolidine ring. Here we describe observation of the IPNS reaction in crystals by X-ray crystallography. IPNS Fe2+ substrate crystals were grown anaerobically, exposed to high pressures of oxygen to promote reaction and frozen, and their structures were elucidated by X-ray diffraction. Using the natural substrate ACV, this resulted in the IPNS x Fe2+ x IPN product complex. With the substrate analogue, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-L-S-methylcysteine (ACmC) in the crystal, the reaction cycle was interrupted at the monocyclic stage. These mono- and bicyclic structures support our hypothesis of a two-stage reaction sequence leading to penicillin. Furthermore, the formation of a monocyclic sulphoxide product from ACmC is most simply explained by the interception of a high-valency iron-oxo species.
Nontoxic Metal-Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis
Publisher: American Chemical Society (ACS)
Date: 07-06-2016
DOI: 10.1021/ACS.JMEDCHEM.6B00432
Abstract: Tuberculosis (TB) accounted for 1.5 million deaths in 2014, and new classes of anti-TB drugs are required. We report a class of functionalized 1,8-disubstituted cyclam derivatives that display low micromolar activity against pathogenic mycobacteria. These compounds inhibit intracellular growth of Mycobacterium tuberculosis, are nontoxic to human cell lines, and are active against multidrug-resistant M. tuberculosis strains, indicating a distinct mode of action. These compounds warrant further appraisal as novel agents to control TB in humans.
Metal Complexes as a Promising Source for New Antibiotics
Publisher: American Chemical Society (ACS)
Date: 15-10-2019
DOI: 10.26434/CHEMRXIV.9956744.V1
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Metal Complexes as a Promising Source for New Antibiotics
Publisher: American Chemical Society (ACS)
Date: 22-10-2019
DOI: 10.26434/CHEMRXIV.9956744.V2
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant S. aureus (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2MD00150K
Abstract: Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis ( Mtb ). Carborane pendants enhance this activity.
Chemical sensors that incorporate click-derived triazoles
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0CS00143K
Abstract: Since the advent of click chemistry in 2001, the 1,4-disubstituted triazole has become an increasingly common motif in chemical sensors. Although these click-derived triazoles are generally used as a convenient method of ligation, their prevalence in chemosensors can be attributed to their ability to bind both cations and anions. In this critical review, we present an overview of the wide range of chemosensors that contain click-derived triazoles, with a particular focus on those cases where the triazole plays a functional, rather than merely a structural, role. Ex les are categorised based on method of detection and key structural features, providing a complete picture of the current state of click-based chemosensors, as well as potential future directions for sensor design. (140 references).
Using click chemistry to tune the properties and the fluorescence response mechanism of structurally similar probes for metal ions
Publisher: Wiley
Date: 05-12-2015
Crystallographic studies on the reaction of isopenicillin N synthase with an unsaturated substrate analogue
Publisher: Royal Society of Chemistry (RSC)
Date: 21-03-2003
DOI: 10.1039/B212270G
Abstract: Isopenicillin N synthase (IPNS) catalyses conversion of the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN), the central step in biosynthesis of the beta-lactam antibiotics. The unsaturated substrate analogue delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-vinylglycine (ACvG) has previously been incubated with IPNS and single product was isolated, a 2-alpha-hydroxymethyl isopenicillin N (HMPen), formed via a monooxygenase mode of reactivity. ACvG has now been crystallised with IPNS and the structure of the anaerobic IPNS:Fe(II):ACvG complex determined to 1.15 A resolution. Furthermore, by exposing the anaerobically grown crystals to high-pressure oxygen gas, a structure corresponding to the bicyclic product HMPen has been obtained at 1.60 A resolution. In light of these and other IPNS structures, and recent developments with related dioxygenases, the [2 + 2] cycloaddition mechanism for HMPen formation from ACvG has been revised, and a stepwise radical mechanism is proposed. This revised mechanism remains consistent with the observed stereospecificity of the transformation, but fits better with apparent constraints on the coordination geometry around the active site iron atom.
Centralised and portable 'network forensics' using smartphone-based diagnostics: Case study - The mapping of tap water pH across Sydney, Australia
Publisher: IEEE
Date: 12-2014
Crystallographic studies on the binding of selectively deuterated LLD- and LLL-substrate epimers by isopenicillin N synthase
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.BBRC.2010.06.129
Abstract: Isopenicillin N synthase (IPNS) is a non-heme iron(II) oxidase which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV). Herein we report crystallographic studies to investigate the binding of a truncated lll-substrate in the active site of IPNS. Two epimeric tripeptides have been prepared by solution phase peptide synthesis and crystallised with the enzyme. delta-l-alpha-Aminoadipoyl-l-cysteinyl-d-2-amino-3,3-dideuteriobutyrate (lld-ACd(2)Ab) has the same configuration as the natural substrate lld-ACV at each of its three stereocentres its epimer delta-l-alpha-aminoadipoyl-l-cysteinyl-l-2-amino-3,3-dideuteriobutyrate (lll-ACd(2)Ab) has the opposite configuration at its third amino acid. lll-ACV has previously been shown to inhibit IPNS turnover of its substrate lld-ACV the all-protiated tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-2-aminobutyrate (lld-ACAb) is a substrate for IPNS, being turned over to a mixture of penam and cepham products. Comparisons between the crystal structures of the IPNS:Fe(II):lld-ACd(2)Ab and IPNS:Fe(II):lll-ACd(2)Ab complexes offer a possible rationale for the previously observed inhibitory effects of lll-ACV on IPNS activity.
Active-site-mediated elimination of hydrogen fluoride from a fluorinated substrate analogue by isopenicillin N synthase
Publisher: Portland Press Ltd.
Date: 24-08-2004
DOI: 10.1042/BJ20040529
Abstract: Isopenicillin N synthase (IPNS) is a non-haem iron oxidase that catalyses the formation of bicyclic isopenicillin N from δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV). In this study we report a novel activity for the iron of the IPNS active site, which behaves as a Lewis acid to catalyse the elimination of HF from the fluorinated substrate analogue, δ-(L-α-aminoadipoyl)-L-cysteinyl-D-β-fluorovaline (ACβFV). X-Ray crystallographic studies of IPNS crystals grown anaerobically with ACβFV reveal that the valinyl β-fluorine is missing from the active site region, and suggest the presence of the unsaturated tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-isodehydrovaline in place of substrate ACβFV. 19F NMR studies confirm the release of fluoride from ACβFV in the presence of the active IPNS enzyme. These results suggest a new mode of reactivity for the IPNS iron centre, a mechanism of action that has not previously been reported for any of the iron oxidase enzymes.
Symbiosis in chemistry and biology
Publisher: Springer Science and Business Media LLC
Date: 02-2006
Abstract: What do organic synthesis, mechanistic enzymology, structural biology and glycoscience have in common? They all span chemistry and biology, benefit from and contribute to multidisciplinary approaches, and were up for discussion at a recent symposium in Dublin.
Substrate range and enantioselectivity of epoxidation reactions mediated by the ethene-oxidising Mycobacterium strain NBB4
Publisher: Springer Science and Business Media LLC
Date: 14-03-2013
DOI: 10.1007/S00253-012-3975-6
Abstract: Mycobacterium strain NBB4 is an ethene-oxidising micro-organism isolated from estuarine sediments. In pursuit of new systems for biocatalytic epoxidation, we report the capacity of strain NBB4 to convert a erse range of alkene substrates to epoxides. A colorimetric assay based on 4-(4-nitrobenzyl)pyridine) has been developed to allow the rapid characterisation and quantification of biocatalytic epoxide synthesis. Using this assay, we have demonstrated that ethene-grown NBB4 cells epoxidise a wide range of alkenes, including terminal (propene, 1-butene, 1-hexene, 1-octene and 1-decene), cyclic (cyclopentene, cyclohexene), aromatic (styrene, indene) and functionalised substrates (allyl alcohol, dihydropyran and isoprene). Apparent specific activities have been determined and range from 2.5 to 12.0 nmol min(-1) per milligram of cell protein. The enantioselectivity of epoxidation by Mycobacterium strain NBB4 has been established using styrene as a test substrate (R)-styrene oxide is produced in enantiomeric excesses greater than 95%. Thus, the ethene monooxygenase of Mycobacterium NBB4 has a broad substrate range and promising enantioselectivity, confirming its potential as a biocatalyst for alkene epoxidation.
Incorporating a piperidinyl group in the fluorophore extends the fluorescence lifetime of click-derived cyclam-naphthalimide conjugates
Publisher: Public Library of Science (PLoS)
Date: 07-2014
Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis
Publisher: American Chemical Society (ACS)
Date: 20-11-2018
DOI: 10.1021/ACS.JMEDCHEM.8B01533
Abstract: Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead c aigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
Structural Studies on the Reaction of Isopenicillin N Synthase with the Truncated Substrate Analogues δ-(l -α-aminoadipoyl)-l -cysteinyl-glycine and δ-(l -α-aminoadipoyl)
Publisher: American Chemical Society (ACS)
Date: 08-04-2005
DOI: 10.1021/BI047478Q
Abstract: Isopenicillin N synthase (IPNS), a non-heme iron(II)-dependent oxidase, catalyzes conversion of the tripeptide delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to bicyclic isopenicillin N (IPN), concomitant with the reduction of dioxygen to two molecules of water. Incubation of the "truncated"substrate analogues delta-(l-alpha-aminoadipoyl)-l-cysteinyl-glycine (ACG) and delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-alanine (ACA) with IPNS has previously been shown to afford acyclic products, in which the substrate cysteinyl residue has undergone a two-electron oxidation. We report X-ray crystal structures for the anaerobic IPNS/Fe(II)/ACG and IPNS/Fe(II)/ACA complexes, both in the absence and presence of the dioxygen analogue nitric oxide. The overall protein structures are very similar to those of the corresponding IPNS/Fe(II)/ACV complexes however, significant differences are apparent in the vicinity of the active site iron. The structure of the IPNS/Fe(II)/ACG complex reveals that the C-terminal carboxylate of this substrate is oriented toward the active site iron atom, apparently hydrogen-bonded to an additional water ligand at the metal this is a different binding mode to that observed in the IPNS/Fe(II)/ACV complex. ACA binds to the metal in a manner that is intermediate between those observed for ACV and ACG. The addition of NO to these complexes initiates conformational changes such that both the IPNS/Fe(II)/ACG/NO and IPNS/Fe(II)/ACA/NO structures closely resemble the IPNS/Fe(II)/ACV/NO complex. These results further demonstrate the feasibility of metal-centered rearrangements in catalysis by non-heme iron enzymes and provide insight into the delicate balance between hydrophilic-hydrophobic interactions and steric effects in the IPNS active site.
Bengamides display potent activity against drug-resistant Mycobacterium tuberculosis
Publisher: Springer Science and Business Media LLC
Date: 07-10-2019
DOI: 10.1038/S41598-019-50748-2
Abstract: Mycobacterium tuberculosis infects over 10 million people annually and kills more people each year than any other human pathogen. The current tuberculosis (TB) vaccine is only partially effective in preventing infection, while current TB treatment is problematic in terms of length, complexity and patient compliance. There is an urgent need for new drugs to combat the burden of TB disease and the natural environment has re-emerged as a rich source of bioactive molecules for development of lead compounds. In this study, one species of marine sponge from the Tedania genus was found to yield s les with exceptionally potent activity against M. tuberculosis . Bioassay-guided fractionation identified bengamide B as the active component, which displayed activity in the nanomolar range against both drug-sensitive and drug-resistant M. tuberculosis . The active compound inhibited in vitro activity of M. tuberculosis MetAP1c protein, suggesting the potent inhibitory action may be due to interference with methionine aminopeptidase activity. Tedania -derived bengamide B was non-toxic against human cell lines, synergised with rif icin for in vitro inhibition of bacterial growth and reduced intracellular replication of M. tuberculosis . Thus, bengamides isolated from Tedania sp . show significant potential as a new class of compounds for the treatment of drug-resistant M. tuberculosis .
The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues δ-(L-α-Aminoadipoyl)-L-homocysteinyl-D-Xaa Characterised by Protein Crystallography
Publisher: Wiley
Date: 06-03-2013
Abstract: Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a erse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe(II):AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe(II):AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures.
Time-resolved and temperature tuneable measurements of fluorescent intensity using a smartphone fluorimeter.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7AN00535K
Abstract: A smartphone fluorimeter is demonstrated for steady-state and time-resolved fluorescence intensity measurements at tunable temperatures.
Antitubercular Bis-Substituted Cyclam Derivatives: Structure–Activity Relationships and in Vivo Studies
Publisher: American Chemical Society (ACS)
Date: 20-03-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01569
Abstract: We recently reported the discovery of nontoxic cyclam-derived compounds that are active against drug-resistant Mycobacterium tuberculosis. In this paper we report exploration of the structure-activity relationship for this class of compounds, identifying several simpler compounds with comparable activity. The most promising compound identified, possessing significantly improved water solubility, displayed high levels of bacterial clearance in an in vivo zebrafish embryo model, suggesting this compound series has promise for in vivo treatment of tuberculosis.
Bend and twist intramolecular charge transfer and emission for selective metal ion sensing
Publisher: The Optical Society
Date: 27-10-2015
DOI: 10.1364/OME.5.002675
A Click Fluorophore Sensor that Can Distinguish CuII and HgII via Selective Anion‐Induced Demetallation
Publisher: Wiley
Date: 08-02-2011
Abstract: A cyclam-based fluorescent sensor featuring a novel triazole pendant arm has been synthesised using click chemistry. The sensor is highly responsive to both Cu(II) and Hg(II) in neutral aqueous solution and displays excellent selectivity in the presence of various competing metal ions in 50-fold excess. The addition of specific anions such as I(-) and S(2)O(3)(2-) causes a complete revival of fluorescence only in the case of Hg(II), providing a simple and effective method for distinguishing solutions containing Cu(II), Hg(II) or a mixture of both ions, even in doped seawater s les. X-ray crystal structures of both the Hg(II) sensor complex and a model Cu(II) complex show that pendant triazole coordination occurs through the central nitrogen atom (N2), providing to the best of our knowledge the first reported ex les of this unusual coordination mode in macrocycles. Fluorescence, mass spectrometry and (1)H NMR experiments reveal that the mechanism of anion-induced fluorescence revival involves either displacement of pendant coordination or complete removal of the Hg(II) from the macrocycle, depending on the anion.
Design and synthesis of a tetradentate '3-amine-1-carboxylate' ligand to mimic the metal binding environment at the non-heme iron(ii) oxidase active site
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B921934J
Abstract: Non-heme iron(II) oxidases (NHIOs) catalyse a erse array of oxidative chemistry in Nature. As part of ongoing efforts to realize biomimetic, iron-mediated C-H activation, we report the synthesis of a new 'three-amine-one-carboxylate' ligand designed to complex with iron(II) and mimic the NHIO active site. The tetradentate ligand has been prepared as a single enantiomer in nine synthetic steps from N-Cbz-L-alanine, pyridine-2,6-dimethanol and diphenylamine, using Seebach oxazolidinone chemistry to control the stereochemistry. X-Ray crystal structures are reported for two important intermediates, along with variable temperature NMR experiments to probe the hindered interconversion of conformational isomers of several key intermediates, 2,6-disubstituted pyridine derivatives. The target ligand and an N-Cbz-protected precursor were each then complexed with iron(II) and tested for their ability to promote alkene dihydroxylation, using hydrogen peroxide as the oxidant.
Synthesis and Evaluation of 1,8-Disubstituted-Cyclam/Naphthalimide Conjugates as Probes for Metal Ions
Publisher: Wiley
Date: 08-2016
Reversing the triazole topology in a cyclam-triazole-dye ligand gives a 10-fold brighter signal response to Zn 2+ in aqueous solution
Publisher: Wiley
Date: 25-10-2012
Synthesis, electrochemistry and metal binding properties of monosubstituted ferrocenoyl peptides with thioether-containing sidechains
Publisher: Elsevier BV
Date: 02-2011
Meet the Medicines—A Crowdsourced Approach to Collecting and Communicating Information about Essential Medicines Online
Publisher: MDPI AG
Date: 27-02-2023
Abstract: The World Health Organization (WHO) maintains a list of medicines and medical devices, essential medicines, that should be available to everyone, to form a functioning healthcare system. Yet, many of these medicines remain out of reach for people around the world. One significant barrier to improving the accessibility of essential medicines is a paucity of information about both the extent and causes of this problem. E$$ENTIAL MEDICINE$ (E$$) is a citizen science project designed to investigate this deficit of information by recruiting members of the public to find, validate, compile and share information on essential medicines through an open, online database. Herein, we report an approach to crowdsourcing both the collection of information on the accessibility of essential medicines and the subsequent communication of these findings to erse audiences. The Meet the Medicines initiative encourages members of the public to share information from the E$$ database, in a short video format appropriate for social media. This communication details the design and implementation of our crowdsourced approach and strategies for recruiting and supporting participants. We discuss data on participant engagement, consider the benefits and challenges of this approach and suggest ways to promote crowdsourcing practices for social and scientific good.
Copper(ii ) complexes of N-propargyl cyclam ligands reveal a range of coordination modes and colours, and unexpected reactivity
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0DT03736B
Abstract: Copper( ii ) complexes of cyclam ligands with 1, 2, 3 or 4 pendant alkynes have been prepared and characterised crystallographically and spectroscopically. An unexpected hydroalkoxylation reaction is observed, affording an enol ether from the alkyne.
Recent advances in macrocyclic fluorescent probes for ion sensing
Publisher: MDPI AG
Date: 25-01-2017
Bio-inspired nitrile hydration by peptidic ligands based on L-cysteine, L-methionine or L-penicillamine and pyridine-2,6-dicarboxylic acid
Publisher: MDPI AG
Date: 12-12-2014
Unique binding of a non-natural L,L,L-substrate by isopenicillin N synthase
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.BBRC.2005.08.155
Abstract: Isopenicillin N synthase (IPNS) is a non-haem iron oxidase that catalyses the formation of isopenicillin N from the tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine. In this report, we describe the crystal structure of the enzyme with a non-natural L,L,L-tripeptide substrate, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-L-3,3,3,3',3',3'-hexafluorovaline. This structure reveals a strong binding interaction of the tripeptide within the active site and a unique conformation for the non-natural L,L,L-diastereomer. Taken together, these findings provide a possible rationale for the previously observed inhibitory effects of L,L,L-tripeptide substrates on IPNS activity.
Discovery of microbial natural products by activation of silent biosynthetic gene clusters
Publisher: Springer Science and Business Media LLC
Date: 29-06-2015
DOI: 10.1038/NRMICRO3496
Abstract: Microorganisms produce a wealth of structurally erse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens however, realizing this potential has been h ered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products.
Cyclobutanone Analogues of β-Lactam Antibiotics: β-Lactamase Inhibitors with Untapped Potential?
Publisher: Wiley
Date: 07-02-2017
Abstract: β-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β-lactams: the prolonged, widespread (and at times reckless) use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N is substituted by a tertiary C-H α to a ketone. Cyclobutanone analogues of various β-lactam antibiotics have been investigated over the last 35 years, initially as prospective antibiotics in their own right and inhibitors of the β-lactamase enzymes that impart resistance to β-lactams. More recently they have been tested as inhibitors of other serine proteases and as mechanistic probes of β-lactam biosynthesis. Cyclobutanone analogues of the penam ring system are the first reversible inhibitors with moderate activity against all classes of β-lactamase other compounds from this family inhibit Streptomyces R61 dd-carboxypeptidase/transpeptidase, human neutrophil elastase and porcine pancreatic elastase. But has their potential as enzyme inhibitors been fully exploited? Challenges in synthesising ersely functionalised cyclobutanone derivatives mean that only a limited number have been made (with limited structural ersity) and evaluated. This review surveys the different synthetic approaches that have been taken to these compounds, the investigations made to evaluate their biological activity and prospects for future developments in this area.
The crystal structure of isopenicillin N synthase with δ-(l-α- aminoadipoyl)-l-cysteinyl-d-methionine reveals thioether coordination to iron
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.ABB.2011.09.014
Abstract: Isopenicillin N synthase (IPNS) catalyses cyclization of δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to isopenicillin N (IPN), the central step in penicillin biosynthesis. Previous studies have shown that IPNS turns over a wide range of substrate analogues in which the valine residue of its natural substrate is replaced with other amino acids. IPNS accepts and oxidizes numerous substrates that bear hydrocarbon sidechains in this position, however the enzyme is less tolerant of analogues presenting polar functionality in place of the valinyl isopropyl group. We report a new ACV analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-d-methionine (ACM), which incorporates a thioether in place of the valinyl sidechain. ACM has been synthesized using solution phase methods and crystallized with IPNS. A crystal structure has been elucidated for the IPNS:Fe(II):ACM complex at 1.40Å resolution. This structure reveals that ACM binds in the IPNS active site such that the sulfur atom of the methionine thioether binds to iron in the oxygen binding site at a distance of 2.57Å. The sulfur of the cysteinyl thiolate sits 2.36Å from the metal.
l-Proline-derived ligands to mimic the ‘2-His-1-carboxylate’ triad of the non-haem iron oxidase active site
Publisher: Elsevier BV
Date: 04-2012
Incorporation of bulky and cationic cyclam-triazole moieties into marimastat can generate potent MMP inhibitory activity without inducing cytotoxicity
Publisher: Wiley
Date: 06-2013
L-Proline derived mimics of the non-haem iron active site catalyse allylic oxidation in acetonitrile solutions
Publisher: Elsevier BV
Date: 03-2013
A cyclobutanone analogue mimics penicillin in binding to isopenicillin N synthase
Publisher: Wiley
Date: 23-10-2007
Abstract: A carbocyclic analogue of the beta-lactam antibiotic isopenicillin N (IPN) has been synthesised and cocrystallised with isopenicillin N synthase (IPNS), the central enzyme in the biosynthesis of penicillin antibiotics. The crystal structure of the IPNS-cyclobutanone complex reveals an active site environment similar to that seen in the enzyme-product complex generated by turnover of the natural substrate within the crystalline protein. The IPNS-cyclobutanone structure demonstrates that the product analogue is tethered to the protein by hydrogen bonding and salt bridge interactions with its carboxylate groups, as seen previously for the natural substrate and product. Furthermore, the successful cocrystallisation of this analogue with IPNS provides firm structural evidence for the utility of such cyclobutanone derivatives as hydrolytically stable analogues of bicyclic beta-lactams.
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
Publisher: Research Square Platform LLC
Date: 27-07-2023
DOI: 10.21203/RS.3.RS-3198291/V1
Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow r -up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure activity relationship and the selectivity mechanism.
Alternative oxidation by isopenicillin N synthase observed by X-ray diffraction
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S1074-5521(01)00090-4
Abstract: Isopenicillin N synthase (IPNS) catalyses formation of bicyclic isopenicillin N, precursor to all penicillin and cephalosporin antibiotics, from the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine. IPNS is a non-haem iron(II)-dependent enzyme which utilises the full oxidising potential of molecular oxygen in catalysing the bicyclisation reaction. The reaction mechanism is believed to involve initial formation of the beta-lactam ring (via a thioaldehyde intermediate) to give an iron(IV)-oxo species, which then mediates closure of the 5-membered thiazolidine ring. Here we report experiments employing time-resolved crystallography to observe turnover of an isosteric substrate analogue designed to intercept the catalytic pathway at an early stage. Reaction in the crystalline enzyme-substrate complex was initiated by the application of high-pressure oxygen, and subsequent flash freezing allowed an oxygenated product to be trapped, bound at the iron centre. A mechanism for formation of the observed thiocarboxylate product is proposed. In the absence of its natural reaction partner (the N-H proton of the L-cysteinyl-D-valine amide bond), the proposed hydroperoxide intermediate appears to attack the putative thioaldehyde species directly. These results shed light on the events preceding beta-lactam closure in the IPNS reaction cycle, and enhance our understanding of the mechanism for reaction of the enzyme with its natural substrate.
Contrasting fates for 6-α-methylpenicillin N upon oxidation by deacetoxycephalosporin C synthase (DAOCS) and deacetoxy/deacetylcephalosporin C synthase (DAOC/DACS)
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0960-894X(01)00470-X
Abstract: 6-alpha-methylpenicillin N was synthesised via known routes from 6-aminopenicillanic acid, and tested as a substrate for recombinant DAOCS and DAOC/DACS. Incubation with DAOCS resulted in conversion of 2-oxoglutarate without oxidation of the penicillin substrate ('uncoupled turnover'). Incubation with DAOC/DACS resulted in oxidation to the cephem aldehyde. This is the first ex le of substrate-induced 'uncoupled turnover', which has been proposed to be an editing mechanism for these enzymes.
Copper(II) Complexes of N-Propargyl Cyclam Ligands Reveal a Range of Coordination Modes and Colours, and Unexpected Reactivity
Publisher: American Chemical Society (ACS)
Date: 02-07-2020
DOI: 10.26434/CHEMRXIV.12592418.V1
Abstract: Herein we describe single crystal X-ray diffraction and spectroscopic investigations of the coordination chemistry of copper(II) complexes of cyclam derivatives with between 1 and 4 pendant alkynes. The crystal structures of these copper complexes unexpectedly reveal a range of coordination modes, and the surprising occurrence of five unique complexes within a single recrystallisation of the tetra- N -propargyl cyclam ligand. One of these species exhibits weak intramolecular copper-alkyne coordination, and another is formed by a surprising intramolecular copper-mediated hydroalkoxylation reaction with the solvent methanol, transforming one of the pendant alkynes to an enol ether. Multiple functionalisation of the tetra- N -propargyl ligand is demonstrated via a ‘tetra-click’ reaction with benzyl azide, and the copper-binding behaviour of the resulting tetra-triazole ligand is characterised spectroscopically.
Yeppoonic acids A – D: 1,2,4-trisubstituted arene carboxylic acid co-metabolites of conglobatin from an Australian Streptomyces sp.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2022
DOI: 10.1038/S41429-021-00493-4
Abstract: Streptomyces sp. MST-91080 was isolated from a soil s le collected in Queensland, Australia. From this strain, yeppoonic acids A - D were purified and spectroscopically characterised. The yeppoonic acids are a family of diene enecarboxylic acids on a 1,2,4-trisubstituted benzene scaffold, structurally related to other Streptomyces secondary metabolites MF-EA-705α/β, NFAT-133 and the lorneic acids. Yeppoonic acids B and C show strong cytotoxicity against the NS-1 mouse myeloma cell line (IC
Unexpected oxidation of a depsipeptide substrate analogue in crystalline isopenicillin N synthase
Publisher: Wiley
Date: 30-01-2006
Abstract: Isopenicillin N synthase (IPNS) is a non-heme iron(ii)-dependent oxidase that is central to penicillin biosynthesis. Herein, we report mechanistic studies of the IPNS reaction in the crystalline state, using the substrate analogue delta-(L-alpha-aminoadipoyl)-(3R)-methyl-L-cysteine D-alpha-hydroxyisovaleryl ester (AmCOV) to probe the early stages of the catalytic cycle. The X-ray crystal structure of the anaerobic IPNS:Fe(II):AmCOV complex was solved to 1.40 A resolution, and it reveals several subtle differences in the active site relative to the complex of the enzyme with its natural substrate. The crystalline IPNS:Fe(II):AmCOV complex was then exposed to oxygen gas at high pressure this brought about reaction to give what appears to be a hydroxymethyl/ene-thiol product. A mechanism for this reaction is proposed. These results offer further insight into the delicate interplay of steric and electronic effects in the IPNS active site and the mechanistic intricacies of this remarkable enzyme.
Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic
Publisher: American Chemical Society (ACS)
Date: 23-11-2011
DOI: 10.1021/IC2020012
Abstract: We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen "click" reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino acid stereocenters. However, a methylene group adjacent to the triazole is susceptible to H/D exchange under ambient conditions, an observation which has potentially important implications for structures involving stereocenters adjacent to triazoles in click-derived structures. The successful incorporation of several amino acids is described, including reactive tryptophan and cysteine side chains. All complexes are formed rapidly upon introduction of the relevant metal salt, including synthetically convenient cases where trifluoroacetate salts of cyclam derivatives are used directly in the metalation. None of the metal complexes displayed any cytotoxicity to mammalian cells, suggesting that the attachment of such complexes to amino acids and peptides does not induce toxicity, further supporting their potential suitability for labeling/imaging studies. One Cu(II)-cyclam-triazole-cysteine disulfide complex displayed moderate activity against MCF-10A breast nontumorigenic epithelial cells.
Suertides A–C: selective antibacterial cyclic hexapeptides from Amycolatopsis sp. MST-135876v3
Publisher: Springer Science and Business Media LLC
Date: 26-07-2022
DOI: 10.1038/S41429-022-00544-4
Abstract: Amycolatopsis sp. MST-135876 was isolated from soil collected from the riverbank of El Pont de Suert, Catalonia, Spain. Cultivation of MST-135876 on a range of media led to the discovery of a previously unreported dichlorinated cyclic hexapeptide, suertide A ( d -Ser, 5-Cl- d -Trp, 6-Cl- d -Trp, l -Ile, d -Val, d -Glu), featuring an unprecedented pair of adjacent 5/6-chlorotryptophan residues. Supplementing the growth medium with KBr resulted in production of the mono- and dibrominated analogues suertides B and C, respectively. Suertides A–C displayed selective activity against Bacillus subtilis (MIC 1.6 µg ml −1 ) and Staphylococcus aureus (MIC 3.1, 6.3, and 12.5 µg ml −1 , respectively), while suertides A and B showed appreciable activity against methicillin-resistant S. aureus (MIC 1.6 and 6.3 µg ml −1 , respectively).
Isopenicillin N synthase
Publisher: The Royal Society of Chemistry
Date: 06-05-2015
DOI: 10.1039/9781782621959-00414
Abstract: Isopenicillin N synthase (IPNS) catalyses the oxidative bicyclization of δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) to form isopenicillin N (IPN), a conversion that is essential in the biosynthesis of penicillin and cephalosporin antibiotics. IPNS uses the full oxidizing potential of molecular oxygen to drive this reaction, forming new C–N and C–S bonds and reducing O2 to two molecules of water. IPNS does not use 2-oxoglutarate (2OG) or any co-substrate other than O2, but has sequence homology along with structural and mechanistic similarities to the 2OG-dependent oxygenase family. The chemically challenging reaction that IPNS catalyses and the central role it plays in antibiotic biosynthesis mean that IPNS has been studied extensively over many years. Crystal structures for the substrate-free enzyme, enzyme–substrate and enzyme–product complexes have all been described, and key intermediates have been trapped chemically and characterized crystallographically as well. This structural information combines with a erse array of solution phase turnover experiments and spectroscopic studies to provide a detailed picture of IPNS catalysis.
A device for the high-pressure oxygenation of protein crystals
Publisher: Elsevier BV
Date: 09-2002
DOI: 10.1016/S0003-2697(02)00246-4
Abstract: A system has been developed for subjecting protein crystals to hyperbaric pressures of oxygen gas in order to promote enzymatic reaction. Crystals of an oxygenase or oxidase enzyme are grown anaerobically by hanging drop vapor diffusion, under crystallization conditions modified to eliminate combustible materials such as plastic coverslips and grease. The crystalline enzyme:substrate complex can then be exposed to oxygen gas at pressures up to 60 bar using a custom-built device or "bomb." In this way, reaction is initiated synchronously throughout the crystal and subsequent flash freezing allows the trapping of enzyme:product complexes in high occupancy. These complexes can then be structurally characterized by conventional monochromatic X-ray crystallography. The bomb is furnished from naval brass and lubricated with Fomblin RT15 perfluorinated polyether grease in order to ensure compatibility with the highly oxidizing environment.
Metal complexes as a promising source for new antibiotics
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9SC06460E
Abstract: There is a dire need for new compounds to combat antibiotic resistance: metal complexes might provide the solution. 906 metal complexes were evaluated against dangerous ESKAPE pathogens and found to have a higher hit-rate than organic molecules.
Neuroprotective peptide–macrocycle conjugates reveal complex structure–activity relationships in their interactions with amyloid β
Publisher: Oxford University Press (OUP)
Date: 2014
DOI: 10.1039/C4MT00122B
Abstract: Novel neuroprotective peptide–macrocycle conjugates exhibit complex, multifaceted structure–activity relationships in their interactions with amyloid β.
Inhibition studies of Mycobacterium tuberculosis salicylate synthase (MbtI)
Publisher: Wiley
Date: 25-06-2010
Abstract: Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This complex secondary metabolite is essential for both virulence and survival of M. tuberculosis, the etiological agent of tuberculosis (TB). It is therefore anticipated that inhibitors of this enzyme may serve as TB therapies with a novel mode of action. Herein we describe the first inhibition study of M. tuberculosis MbtI using a library of functionalized benzoate-based inhibitors designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the MbtI-catalyzed reaction. The most potent inhibitors prepared were those designed to mimic the enzyme intermediate, isochorismate. These compounds, based on a 2,3-dihydroxybenzoate scaffold, proved to be low-micromolar inhibitors of MbtI. The most potent inhibitors in this series possessed hydrophobic enol ether side chains at C3 in place of the enol-pyruvyl side chain found in chorismate and isochorismate.
The crystal structure of isopenicillin N synthase with a dipeptide substrate analogue
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.ABB.2012.12.012
Abstract: Isopenicillin N synthase (IPNS) converts its linear tripeptide substrate δ-L-α-aminoadipoyl-L-cysteinyl-D-valine (ACV) to bicyclic isopenicillin N (IPN), the key step in penicillin biosynthesis. Solution-phase incubation experiments have shown that IPNS will accept and oxidise a erse array of substrate analogues, including tripeptides that incorporate L-homocysteine as their second residue, and tripeptides with truncated side-chains at the third amino acid such as δ-L-α-aminoadipoyl-L-cysteinyl-D-α-aminobutyrate (ACAb), δ-L-α-aminoadipoyl-L-cysteinyl-D-alanine (ACA) and δ-L-α-aminoadipoyl-L-cysteinyl-glycine (ACG). However IPNS does not react with dipeptide substrates. To probe this selectivity we have crystallised the enzyme with the dipeptide δ-L-α-aminoadipoyl-L-homocysteine (AhC) and solved a crystal structure for the IPNS:Fe(II):AhC complex to 1.40 Å resolution. This structure reveals an unexpected mode of peptide binding at the IPNS active site, in which the homocysteinyl thiolate does not bind to iron. Instead the primary mode of binding sees the homocysteinyl carboxylate coordinated to the metal, while its side-chain is oriented into the region of the active site normally occupied by the benzyl group of protein residue Phe211.
(2S,4S)-3-Benzoyl-4-benzyl-2-tert-butyl-1,3-oxazolidin-5-one
Publisher: International Union of Crystallography (IUCr)
Date: 23-08-2012
Structural studies on the reaction of isopenicillin N synthase with the substrate analogue delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-alpha-aminobutyrate
Publisher: Portland Press Ltd.
Date: 15-06-2003
DOI: 10.1042/BJ20021627
Abstract: Isopenicillin N synthase (IPNS) is a non-haem iron(II) oxidase which catalyses the biosynthesis of isopenicillin N from the tripeptide δ-(l-α-aminoadipoyl)-l-cysteinyl-d-valine (ACV). Herein we report crystallographic studies to investigate the reaction of IPNS with the truncated substrate analogue δ-(l-α-aminoadipoyl)-l-cysteinyl-d-α-aminobutyrate (ACAb). It has been reported previously that this analogue gives rise to three β-lactam products when incubated with IPNS: two methyl penams and a cepham. Crystal structures of the IPNS–Fe(II)–ACAb and IPNS–Fe(II)–ACAb–NO complexes have now been solved and are reported herein. These structures and modelling studies based on them shed light on the diminished product selectivity shown by IPNS in its reaction with ACAb and further rationalize the presence of certain key residues at the IPNS active site.
GitHub as an open electronic laboratory notebook for real-time sharing of knowledge and collaboration
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3DD00032J
Abstract: Sharing scientific experiments and data with the community using GitHub as an electronic laboratory notebook.
Early Warning Smartphone Diagnostics for Water Security and Analysis Using Real-Time pH Mapping
Publisher: Springer Science and Business Media LLC
Date: 23-09-2015
Terminally Truncated Isopenicillin N Synthase Generates a Dithioester Product: Evidence for a Thioaldehyde Intermediate during Catalysis and a New Mode of Reaction for Non‐Heme Iron Oxidases
Publisher: Wiley
Date: 21-08-2017
The crystal structure of an LLL-configured depsipeptide substrate analogue bound to isopenicillin N synthase
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B910170E
Abstract: Isopenicillin N synthase (IPNS) is a non-heme iron(ii) oxidase, which catalyses the biosynthesis of isopenicillin N (IPN) from the tripeptide delta-l-alpha-aminoadipoyl-l-cysteinyl-d-valine (lld-ACV) in a remarkable oxidative bicyclisation reaction. The natural substrate for IPNS is the lld-configured tripeptide. lll-ACV is not turned over by the enzyme, but inhibits turnover of the lld-tripeptide. The mechanism by which this inhibition takes place is not fully understood. Recent studies have employed a range of lld-configured depsipeptide substrate analogues in crystallographic studies to probe events preceding beta-lactam closure in the IPNS reaction cycle. Herein, we report the first crystal structure of IPNS in complex with an lll-configured depsipeptide analogue, delta-l-alpha-aminoadipoyl-l-cysteine (1-(R)-carboxy-2-thiomethyl)ethyl ester (lll-ACOmC). This report describes the crystal structure of the IPNS:Fe(ii):lll-ACOmC complex to 2.0 A resolution, and discusses attempts to oxygenate this complex at high pressure in order to probe the mechanism by which lll-configured substrates inhibit IPNS catalysis.
tele-Substitution Reactions in the Synthesis of a Promising Class of 1,2,4-Triazolo[4,3-a]pyrazine-Based Antimalarials
Publisher: American Chemical Society (ACS)
Date: 13-08-2020
The properties and performance of a pH-responsive functionalised nanoparticle
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4FD00110A
Abstract: We report fluorescence measurements of three quantum dots (QDs) of different sizes functionalised with the same pH responsive naphthalimide dye. QD size strongly influences energy transfer between dye and dot. Using QDs with an emission maximum of 570 nm gives rise to an interesting transfer of energy from dye to dot, while QDs with an emission maximum at 670 nm give unexpected enhancement of the dye emission. Titrations of QDs with the dye provide a means to establish the loading and hence an approximation of the surface dye density, which varies in proportion to QD size. Quenching effects are observed beyond the loading limit, and may indicate non-specific interactions between the excess dye and the nanoparticle. Attachment of the dye to the QD core is achieved by a thiol/disulfide exchange process that has been interrogated with Raman spectroscopy. The stability of these QD–dye conjugates over time and across a physiological pH range has been investigated to provide an assessment of their performance and robustness.
Investigating the oxidation of alkenes by non-heme iron enzyme mimics
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2OB25834J
Abstract: Iron is emerging as a key player in the search for efficient and environmentally benign methods for the functionalisation of C-H bonds. Non-heme iron enzymes catalyse a erse array of oxidative chemistry in nature, and small-molecule complexes designed to mimic the non-heme iron active site have great potential as C-H activation catalysts. Herein we report the synthesis of a series of organic ligands that incorporate key features of the non-heme iron active site. Iron(II) complexes of these ligands have been generated in situ and their ability to promote hydrocarbon oxidation has been investigated. Several of these systems promote the biomimetic dihydroxylation of cyclohexene at low levels, when hydrogen peroxide is used as the oxidant allylic oxidation products are also observed. An investigation of ligand stability reveals formation of several breakdown products under the conditions of the oxidative turnover reactions. These products arise via oxidative decarboxylation, dehydration and deamination reactions. Taken together these results indicate that competing mechanisms are at play with these systems: biomimetic hydroxylation involving high-valent iron species, and allylic oxidation via Fenton chemistry and Haber-Weiss radical pathways.
Absorption and fluorescence spectroscopy on a smartphone
Publisher: SPIE
Date: 07-2015
DOI: 10.1117/12.2184354
Erratum: Metal complexes as a promising source for new antibiotics (Chem. Sci. (2020) 11 (2627-2639) DOI: 10.1039/c9sc06460e)
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC90075C
Abstract: Correction for ‘Metal complexes as a promising source for new antibiotics’ by Angelo Frei et al. , Chem. Sci. , 2020, 11 , 2627–2639.
Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide conjugates with sulfur-containing side chains
Publisher: Elsevier BV
Date: 07-2010
Structural studies on the reaction of isopenicillin N synthase with a sterically demanding depsipeptide substrate analogue
Publisher: Wiley
Date: 12-08-2009
Abstract: Isopenicillin N synthase (IPNS) is a nonheme iron(II)-dependent oxidase that catalyses the central step in penicillin biosynthesis, conversion of the tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). This report describes mechanistic studies using the analogue delta-(L-alpha-aminoadipoyl)-(3S-methyl)-L-cysteine D-alpha-hydroxyisovaleryl ester (A(S)mCOV), designed to intercept the catalytic cycle at an early stage. A(S)mCOV incorporates two modifications from the natural substrate: the second and third residues are joined by an ester, so this analogue lacks the key amide of ACV and cannot form a beta-lactam and the cysteinyl residue is substituted at its beta-carbon, bearing a (3S)-methyl group. It was anticipated that this methyl group will impinge directly on the site in which the co-substrate dioxygen binds. The novel depsipeptide A(S)mCOV was prepared in 13 steps and crystallised with IPNS anaerobically. The 1.65 A structure of the IPNS-Fe(II)-A(S)mCOV complex reveals that the additional beta-methyl group is not oriented directly into the oxygen binding site, but does increase steric demand in the active site and increases disorder in the position of the isovaleryl side chain. Crystals of IPNS-Fe(II)-A(S)mCOV were incubated with high-pressure oxygen gas, driving substrate turnover to a single product, an ene-thiol/C-hydroxylated depsipeptide. A mechanism is proposed for the reaction of A(S)mCOV with IPNS, linking this result to previous crystallographic studies with related depsipeptides and solution-phase experiments with cysteine-methylated tripeptides. This result demonstrates that a (3S)-methyl group at the substrate cysteinyl beta-carbon is not in itself a block to IPNS activity as previously proposed, and sheds further light on the steric complexities of IPNS catalysis.
Synthesis and structural characterisation of amides from picolinic acid and pyridine-2,6-dicarboxylic acid
Publisher: Springer Science and Business Media LLC
Date: 08-05-2015
DOI: 10.1038/SREP09950
Abstract: Coupling picolinic acid (pyridine-2-carboxylic acid) and pyridine-2,6-dicarboxylic acid with N -alkylanilines affords a range of mono- and bis-amides in good to moderate yields. These amides are of interest for potential applications in catalysis, coordination chemistry and molecular devices. The reaction of picolinic acid with thionyl chloride to generate the acid chloride in situ leads not only to the N -alkyl- N -phenylpicolinamides as expected but also the corresponding 4-chloro- N -alkyl- N -phenylpicolinamides in the one pot. The two products are readily separated by column chromatography. Chlorinated products are not observed from the corresponding reactions of pyridine-2,6-dicarboxylic acid. X-Ray crystal structures for six of these compounds are described. These structures reveal a general preference for cis amide geometry in which the aromatic groups ( N -phenyl and pyridyl) are cis to each other and the pyridine nitrogen anti to the carbonyl oxygen. Variable temperature 1 H NMR experiments provide a window on amide bond isomerisation in solution.
tert-Butyldimethylsilanol hemihydrate
Publisher: International Union of Crystallography (IUCr)
Date: 30-05-2008
The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site
Publisher: Wiley
Date: 13-07-2013
DOI: 10.1016/J.FEBSLET.2013.07.016
Abstract: Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of β-lactam antibiotics. IPNS converts the tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the β-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue.
Polyamide-scorpion cyclam lexitropsins selectively bind AT-rich DNA independently of the nature of the coordinated metal
Publisher: Public Library of Science (PLoS)
Date: 09-05-2011
Molecular Switches for any pH: A Systematic Study of the Versatile Coordination Behaviour of Cyclam Scorpionands
Publisher: Wiley
Date: 27-12-2017
Abstract: Molecular switches have many potential applications in nanoscience and biomedicine. Transition metal complexes that can be switched from an inert, unreactive state to a catalytically active one by a simple change in conditions (e.g. pH shift) or by binding to a specific biomolecular target-so-called target-activated metal complexes (TAMCs)-hold particular allure as a means of harnessing the potent but at times indiscriminate reactivity of metal-based drugs. Towards this goal, we have prepared a series of ten structurally related ligands, each of which bears a different pendant side-arm functional group appended to a common macrocyclic core, along with copper(II) and nickel(II) complexes of these cyclam-based "molecular scorpionands". X-ray crystal structures reveal a variety of binding modes between pendant side-arm and metal centre that depend on the constituent donor atoms. To investigate the switchability of side-arm coordination in solution, spectrophotometric pH titrations were carried out for all 20 metal complexes. The majority of the complexes undergo spectroscopic changes that are consistent with a switch in pendant coordination state at a specific pH. This ligand series represents a comprehensive model platform from which to build pH-switchable metal complexes for applications in nanoscience and biomedicine.
A treasure hunt for chemistry
Publisher: American Chemical Society (ACS)
Date: 14-02-2011
DOI: 10.1021/ED100867M
Resorculins: hybrid polyketide macrolides from Streptomyces sp. MST-91080
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2OB02332F
Abstract: The discovery of the resoruclins, new 3,5-dihydroxybenzoic acid containing macrolides for Steptomyces sp. MST-91080, and their putative biosynthetic pathway.
Diketoacid inhibitors of HIV-1 integrase: From L-708,906 to raltegravir and beyond
Publisher: Bentham Science Publishers Ltd.
Date: 03-2012
DOI: 10.2174/092986712799320565
Abstract: HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FDA) for HIV-1 therapy, while elvitegravir (Gilead Sciences/ Japan Tobacco) has reached phase III clinical trials. This review considers the development of DKA-based inhibitors from early screening studies through to the release of raltegravir. SAR data collated from numerous studies are compared and analysed, shedding light on the geometric and electronic requirements for effective binding to HIV-1 integrase. This information will in turn aid the rational design of future generations of integrase inhibitors.
A direct method for the N-tetraalkylation of azamacrocycles
Publisher: Beilstein Institut
Date: 18-11-2016
DOI: 10.3762/BJOC.12.239
Abstract: An efficient protocol for the direct synthesis of N -tetraalkylated derivatives of the azamacrocycles cyclam and cyclen has been developed, using a partially miscible aqueous–organic solvent system with propargyl bromide, benzyl bromide, and related halides. The method works most effectively when the reaction mixture is shaken, not stirred. A crystal structure of the N -tetrapropargyl cyclam derivative 1,4,8,11-tetra(prop-2-yn-1-yl)-1,4,8,11-tetraazacyclotetradecane diperchlorate is reported.
Isopenicillin N synthase mediates thiolate oxidation to sulfenate in a depsipeptide substrate analogue: Implications for oxygen binding and a link to nitrile hydratase?
Publisher: American Chemical Society (ACS)
Date: 12-07-2008
DOI: 10.1021/JA8005397
Abstract: Isopenicillin N synthase (IPNS) is a nonheme iron oxidase that catalyzes the central step in the biosynthesis of beta-lactam antibiotics: oxidative cyclization of the linear tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to isopenicillin N (IPN). The ACV analogue delta-L-alpha-aminoadipoyl-L-cysteine (1-(S)-carboxy-2-thiomethyl)ethyl ester (ACOmC) has been synthesized as a mechanistic probe of IPNS catalysis and crystallized with the enzyme. The crystal structure of the anaerobic IPNS/Fe(II)/ACOmC complex was determined to 1.80 A resolution, revealing a highly congested active site region. By exposing these anaerobically grown crystals to high-pressure oxygen gas, an unexpected sulfenate product has been observed, complexed to iron within the IPNS active site. A mechanism is proposed for formation of the sulfenate-iron complex, and it appears that ACOmC follows a different reaction pathway at the earliest stages of its reaction with IPNS. Thus it seems that oxygen (the cosubstrate) binds in a different site to that observed in previous studies with IPNS, displacing a water ligand from iron in the process. The iron-mediated conversion of metal-bound thiolate to sulfenate has not previously been observed in crystallographic studies with IPNS. This mode of reactivity is of particular interest when considered in the context of another family of nonheme iron enzymes, the nitrile hydratases, in which post-translational oxidation of two cysteine thiolates to sulfenic and sulfinic acids is essential for enzyme activity.
Fluorescent measurements of Zn2+ on a smartphone
Publisher: SPIE
Date: 07-2015
DOI: 10.1117/12.2184246
pH-Responsive quantum dots (RQDs) that combine a fluorescent nanoparticle with a pH-sensitive dye
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4CP03914A
Abstract: A quantum dot conjugated to a dye through an experimentally simple process of self-assembly exhibits an enhanced emission when the dye is attached, and this effect is pH-sensitive.
A Fluorescent Allosteric Scorpionand Complex Visualizes a Biological Recognition Event
Publisher: Wiley
Date: 09-01-2013
Abstract: We describe a new class of fluorescent reporter and its employment to visualize the biotin/avidin binding interaction. Derivatives of the azamacrocycle cyclam that contain a pendant naphthalimide dye are inherently fluorescent when zinc(II) is coordinated. Introducing a second pendant group--biotin--affords an unsymmetrical bis-triazole-scorpionand ligand that interacts specifically with avidin. This ligand has been assembled by using a one-pot "double-click" strategy and complexed with copper(II) and zinc(II). The zinc(II) complex is fluorescent, and its fluorescence output changes in the presence of avidin. Upon avidin binding, the fluorescence output is diminished by interaction with the protein, at [complex]/[avidin] ratios of up to 4:1. The observed change might arise from a specific quenching effect in the biotin binding pocket or from a binding-induced change in the coordination geometry of the complex.
Metal Complexes as a Promising Source for New Antibiotics
Publisher: American Chemical Society (ACS)
Date: 22-10-2019
DOI: 10.26434/CHEMRXIV.9956744
Abstract: There is a dire need for new classes of antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Antibiotic compounds are notorious for not having very “drug-like” chemical structures. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant i S. aureus /i (MRSA). This work reveals the vast ersity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
Perphenazine–Macrocycle Conjugates Rapidly Sequester the Aβ42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid
Publisher: American Chemical Society (ACS)
Date: 21-12-2022
Chemistry in the Time of COVID-19: Reflections on a Very Unusual Semester
Publisher: American Chemical Society (ACS)
Date: 17-08-2020
Mercury binding by ferrocenoyl peptides with sulfur-containing side chains: Electrochemical, spectroscopic and structural studies
Publisher: Elsevier BV
Date: 08-2008
Synthesis, carbohydrate- and DNA-binding studies of cationic 2,2′:6′,2′′-terpyridineplatinum(ii) complexes containing N- and S-donor boronic acid ligands
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0DT00892C
Abstract: A series of platinum(II) complexes of the type [Pt(trpy)L](NO(3))(n) (L = 3- or 4-pyridineboronic acid (3- or 4-pyB, respectively), n = 2 HL = 4-mercaptophenylboronic acid (HmpB), n = 1 trpy = 2,2':6',2''-terpyridine) and [{Pt(trpy)}(2)(μ-pzB)](NO(3))(3) (HpzB = 4-pyrazoleboronic acid) were synthesized and fully characterized by means of multinuclear ((1)H, (13)C, (11)B, and (195)Pt) 1D- and 2D-NMR spectroscopy and elemental analysis. The triflate derivatives [Pt(trpy)(4-pyB)](OTf)(2) and [{Pt(trpy)}(2)(μ-pzB)](OTf)(3) were also prepared, and their molecular structures were confirmed by X-ray crystallography. Variable pH (1)H NMR spectroscopy showed that hydroxylation of the boronic acid group occurs in aqueous solution at pH > 5 and the pK(a) values for the complexes were determined. In buffered aqueous solution (pH 7.4), the complexes bind strongly to simple diols such as catechol and monosaccharides including D-fructose, D-ribose, D-sorbitol and D-mannitol, as determined by isothermal titration calorimetry (ITC). The equilibrium binding constants for these reactions were determined and were found to exceed those of organic boronic acids such as phenylboronic acid by an order of magnitude or greater, an effect that can be directly attributed to the cationic charge of the complexes. 2D-NMR methods (HSQC and HMBC) were used to elucidate the structures of the carbohydrate adducts [Pt(trpy)(3-pyB)]·D-fructose·NO(3) and [Pt(trpy)(4-pyB)]·D-fructose·NO(3) in aqueous solution. DNA-binding experiments with calf-thymus DNA (CT-DNA) indicate an avid DNA-binding interaction by the mononuclear complexes, as determined using thermal melting methods and ITC, but the behaviour of the dinuclear species [{Pt(trpy)}(2)(μ-pzB)](NO(3))(3) is complicated and could not be modeled adequately higher ionic strength solutions and lower temperatures resulted in a similar DNA binding interaction to the mononuclear complexes. The presence of excess d-fructose did not significantly affect the binding of the platinum(II)-trpy complexes to CT-DNA.
Isopenicillin N Synthase Binds δ-(L-α-Aminoadipoyl)-L-Cysteinyl-D-Thia-allo-Isoleucine through both Sulfur Atoms
Publisher: Wiley
Date: 15-06-2011
Abstract: Isopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non-heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide δ-L-α-aminoadipoyl-L-cysteinyl-D-valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution-phase incubation experiments have shown that, although IPNS can turn over analogues with a erse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts δ-L-α-aminoadipoyl-L-cysteinyl-D-isoleucine (ACI) and AC-D-allo-isoleucine (ACaI) to penam products, the isosteric sulfur-containing peptides AC-D-thiaisoleucine (ACtI) and AC-D-thia-allo-isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:Fe(II) :ACtaI complex to 1.79 Å resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 Å from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates.
Interactions of Isopenicillin N Synthase with Cyclopropyl-Containing Substrate Analogues Reveal New Mechanistic Insight,
Publisher: American Chemical Society (ACS)
Date: 31-03-2007
DOI: 10.1021/BI062314Q
Abstract: Isopenicillin N synthase (IPNS), a non-heme iron oxidase central to penicillin and cephalosporin biosynthesis, catalyzes an energetically demanding chemical transformation to produce isopenicillin N from the tripeptide delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-valine (ACV). We describe the synthesis of two cyclopropyl-containing tripeptide analogues, delta-(l-alpha-aminoadipoyl)-l-cysteinyl-beta-methyl-d-cyclopropylglycine and delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-cyclopropylglycine, designed as probes for the mechanism of IPNS. We have solved the X-ray crystal structures of these substrates in complex with IPNS and propose a revised mechanism for the IPNS-mediated turnover of these compounds. Relative to the previously determined IPNS-Fe(II)-ACV structure, key differences exist in substrate orientation and water occupancy, which allow for an explanation of the differences in reactivity of these substrates.
Temperature controlled portable smartphone fluorimeter
Publisher: OSA
Date: 2014
Design and synthesis of an isopenicillin N synthase mimic
Publisher: Elsevier BV
Date: 2005
Iron complexes of tetramine ligands catalyse allylic hydroxyamination via a nitroso-ene mechanism
Publisher: Beilstein Institut
Date: 11-12-2015
DOI: 10.3762/BJOC.11.275
Abstract: Iron(II) complexes of the tetradentate amines tris(2-pyridylmethyl)amine (TPA) and N , N ′-bis(2-pyridylmethyl)- N , N ′-dimethylethane-1,2-diamine (BPMEN) are established catalysts of C–O bond formation, oxidising hydrocarbon substrates via hydroxylation, epoxidation and dihydroxylation pathways. Herein we report the capacity of these catalysts to promote C–N bond formation, via allylic amination of alkenes. The combination of N -Boc-hydroxylamine with either FeTPA (1 mol %) or FeBPMEN (10 mol %) converts cyclohexene to the allylic hydroxylamine ( tert -butyl cyclohex-2-en-1-yl(hydroxy)carbamate) in moderate yields. Spectroscopic studies and trapping experiments suggest the reaction proceeds via a nitroso–ene mechanism, with involvement of a free N -Boc-nitroso intermediate. Asymmetric induction is not observed using the chiral tetramine ligand (+)-(2 R ,2′ R )-1,1′-bis(2-pyridylmethyl)-2,2′-bipyrrolidine (( R , R ′)-PDP).
Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis
Publisher: Beilstein Institut
Date: 05-11-2019
DOI: 10.3762/BJOC.15.256
Abstract: Chemical investigation of an undescribed Australian fungus, Aspergillus nanangensis , led to the identification of the nanangenines – a family of seven new and three previously reported drimane sesquiterpenoids. The structures of the nanangenines were elucidated by detailed spectroscopic analysis supported by single crystal X-ray diffraction studies. The compounds were assayed for in vitro activity against bacteria, fungi, mammalian cells and plants. Bioinformatics analysis, including comparative analysis with other acyl drimenol-producing Aspergilli, led to the identification of a putative nanangenine biosynthetic gene cluster that corresponds to the proposed biosynthetic pathway for nanangenines.
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