Adam McCluskey

Small molecule Hedgehog pathway antagonists

Publisher: Royal Society of Chemistry (RSC)

Date: 2017

DOI: 10.1039/C6OB01959E

Abstract: Leveraging our quinolone-1-(2 H )-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l -tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1 H -indol-3-yl)-ethyl]-amine.

Crystal Structures of (3R,3aR,4S,7R,7aS)-3-(Allyloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one and (3S,3aR,4S,7R,7aS)-3-((E)-But-2-en-1-yloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one: Confirmation

Publisher: Springer Science and Business Media LLC

Date: 08-02-2012

DOI: 10.1007/S10870-012-0275-Z

N-2-Propenyl-(5-dimethylamino)-1-naphthalene Sulfonamide, a Novel Fluorescent Monomer for the Molecularly Imprinted Polymer-Based Detection of 2,4-Dinitrotoluene in the Gas Phase

Publisher: CSIRO Publishing

Date: 2012

DOI: 10.1071/CH12155

Abstract: Fluorescent molecularly imprinted polymers (MIP) specific for 2,4-dinitrotoluene (DNT) have been synthesised using a novel monomer N-2-propenyl-(5-dimethylamino)-1-naphthalene sulfonamide. Three formats of the polymer were produced: a traditional bulk monolith ground into particles, a flexible, but highly cross-linked plasticiser-modified free standing membrane, and a hybrid material consisting of particles embedded in a poly(acrylonitrile) phase inversed film. Within all materials, a clearly defined imprinting effect was observed upon exposure to DNT vapour at room temperature. In all cases, preferential rebinding of DNT to the molecularly imprinted materials (3–5 times) over their non-imprinted (NIP) equivalents was evident within min of contact with the DNT vapour stream. Fluorographic images of the fluorescent polymers showed the DNT binding-induced quenching to be significantly higher in the MIP material than in the non-imprinted control polymer.

Discovery of acrylonitrile-based small molecules active against Haemonchus contortus

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3MD00255A

An integrated flow and microwave approach to a broad spectrum protein kinase inhibitor

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5RA09426G

Abstract: The protein kinase inhibitor CTx-0152960 and the piperazinyl analogue CTx-0294885 were prepared using a hybrid flow and microwave approach.

Targeting the S100A2‐p53 Interaction with a Series of 3,5‐Bis(trifluoromethyl)benzene Sulfonamides: Synthesis and Cytotoxicity

Publisher: Wiley

Date: 13-07-2021

DOI: 10.1002/CMDC.202000949

Abstract: In silico approaches identified 1 , N ‐(6‐((4‐bromo‐ benzyl)amino)hexyl)‐3,5‐bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of the S100A2‐p53 protein‐protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 μM cell growth inhibitor of the MiaPaCa‐2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti‐pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused library synthesis (three libraries, 24 compounds total) and cytotoxicity screening identified a propyl alkyl diamine spacer as optimal the nature of the terminal phenyl substituent had limited impact on observed cytotoxicity, whereas N ‐methylation was detrimental to activity. In total 15 human cancer cell lines were examined, with most analogues showing broad‐spectrum activity. Near uniform activity was observed against a panel of six pancreatic cancer cell lines: MiaPaCa‐2, BxPC‐3, AsPC‐1, Capan‐2, HPAC and PANC‐1. In all cases there was good to excellent correlation between the predicted docking pose in the S100A2‐p53 binding groove and the observed cytotoxicity, especially in the pancreatic cancer cell line with high endogenous S100A2 expression. This supports S100A2 as a pancreatic cancer drug target.

Focused library development of 2-phenylacrylamides as broad spectrum cytotoxic agents

Publisher: Elsevier BV

Date: 2013

DOI: 10.1016/J.BMC.2012.10.003

Abstract: With our lead compound (E)-3-(4-chlorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (1) inducing 50% growth inhibition of 11 cancer cell lines at 27-61 μM, potency enhancements were rapidly established through the synthesis of a series of focused compound libraries. Six highly focused libraries (46 compounds in total) were synthesised. Each library allowed the identification of a new lead compound, viz Library A identified (E)-3-(pentafluorophenyl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (11) and (E)-3-(1H-indol-3-yl)-2-(1H-pyrrole-2-carbonyl)acrylonitrile (13) as inhibitors with improved cytotoxicity. Synthesis of discrete libraries of amidoacrylamide analogues (Ar-CC(CN)-Ar✠Ar-CC(CN)-C(O)NH)-Ar) resulted in a series of analogues significantly more potent that the lead, 1. Three furan three analogues: (E)-3-(5-chlorofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (33), (E)-3-(5-bromofuran-2-yl)-2-cyano-N-(4-methoxybenzyl)acrylamide (34) and (E)-2-cyano-3-(furan-3-yl)-N-(4-methoxybenzyl)acrylamide (37) returned broad spectrum growth inhibition (GI(50) values of 5-16 μM). Replacement of the furan moiety with simple aromatics gave an additional three analogues: (E)-2-cyano-N-(4-methoxybenzyl)-3-phenylacrylamide (39), (E)-3-(4-chlorophenyl)-2-cyano-N-(4-methoxybenzyl)acrylamide (41) and (E)-2-cyano-N-(4-methoxyphenyl)-3-(naphthalen-1-yl)acrylamide (45) with GI(50) values of 7-24 μM. The final library retained the aromatic substituents but introduced a 3,4-dichlorbenzylamine moiety to afford the 1-naphthyl substituted 52, which was the most potent broad spectrum cytotoxic analogue produced here in with an average GI(50)=8.6 μM. This represents a fivefold potency enhancement relative to 1 and a new cytotoxic scaffold suitable for further development.

The crystal structures of 3-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-6-O-triphenylmethyl-α-D-glucofuranose and its azide displacement product

Publisher: International Union of Crystallography (IUCr)

Date: 31-05-2018

DOI: 10.1107/S205698901800765X

Abstract: The effect of different leaving groups on the substitution versus elimination outcomes with C-5 D-glucose derivatives was investigated. The stereochemical configurations of 3- O -benzyl-1,2- O -isopropylidene-5- O -methanesulfonyl-6- O -triphenylmethyl-α-D-glucofuranose, C 36 H 38 O 8 S ( 3 ) [systematic name: 1-[(3a R ,5 R ,6 S ,6a R )-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3- d ][1,3]dioxol-5-yl)-2-(trityloxy)ethyl methanesulfonate], a stable intermediate, and 5-azido-3- O -benzyl-5-deoxy-1,2- O -isopropylidene-6- O -triphenylmethyl-β-L-idofuranose, C 35 H 35 N 3 O 5 ( 4 ) [systematic name: (3a R ,5 S ,6 S ,6a R )-5-[1-azido-2-(trityloxy)ethyl]-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3- d ][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the molecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3 , neighbouring molecules are linked by C—H...O hydrogen bonds, forming chains along the b -axis direction. The chains are linked by C—H...π interactions, forming layers parallel to the ab plane. In the crystal of 4 , molecules are also linked by C—H...O hydrogen bonds, forming this time helices along the a -axis direction. The helices are linked by a number of C—H...π interactions, forming a supramolecular framework.

A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells

Publisher: American Association for Cancer Research (AACR)

Date: 13-08-2013

DOI: 10.1158/0008-5472.CAN-12-4501

Abstract: The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been h ered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. Cancer Res 73(16) 5169–82. ©2013 AACR.

Robenidine Analogues as Gram-Positive Antibacterial Agents

Publisher: American Chemical Society (ACS)

Date: 10-02-2016

DOI: 10.1021/ACS.JMEDCHEM.5B01797

Abstract: Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 μM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)3 (27) (23.7-71 μM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 μM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 μL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.

Synthesis and Evaluation of a Molecularly Imprinted Polymer Selective to 2,4,6-Trichlorophenol

Publisher: CSIRO Publishing

Date: 2004

DOI: 10.1071/CH04004

Abstract: Molecularly imprinted polymers (MIPs) selective for the phenolic contaminant 2,4,6-trichlorophenol (2,4,6-TCP) were prepared and evaluated in three porogens of differing character (hexane, acetonitrile, dichloromethane). Rebinding of 2,4,6-TCP was found to be most effective in dichloromethane (imprinting factor: 13.2). Competitive binding studies performed against a range of close structural analogues showed a high preference for the target molecule, although partial recognition towards 2,4-dichlorophenol was also observed. Specificity was found to be dependent upon the presence of ring chlorine on the target, which suggested that these atoms participate in secondary binding interactions that are essential for successful recognition in the polymer cavity.

A multicomponent access to 1,3-thiazine-6-phenylimino-5-carboxylates

Publisher: Elsevier BV

Date: 07-2016

DOI: 10.1016/J.TETLET.2016.06.007

Development of quinone analogues as dynamin GTPase inhibitors

Publisher: Elsevier BV

Date: 10-2014

DOI: 10.1016/J.EJMECH.2014.06.070

Abstract: Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.CELL.2011.06.025

Abstract: Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling.

Crystal Structure of Ethyl 2,4-Dimethyl-1-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate: The Product from the Reaction of Ethyl 3-Aminocrotonate, Phenylisothiocyanate and Acetic Anhydride

Publisher: Springer Science and Business Media LLC

Date: 22-05-2018

DOI: 10.1007/S10870-018-0714-6

In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols

Publisher: The Royal Society

Date: 04-2018

DOI: 10.1098/RSOS.171190

Abstract: The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1 , a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally erse β-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of β-amino alcohols 1 and 10a – 18g , resulting in modest ( 11a , 21%) to excellent ( 12g , 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a – 4m (22%–89%) and a Bi(OTf) 3 catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.

The First Two Cantharidin Analogues Displaying PP1 Selectivity

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0960-894X(01)00777-6

Abstract: High pressure Diels-Alder reactions of furan and dimethylmaleate, and thiophene and maleimide resulted in two cantharidin analogues, 3 and 6 possessing PP1 selectivity (>40- and >30-fold selectivity) over PP2A. Both compounds exhibited moderate PP1 activity, 3 IC(50) 50 microM and 6 IC(50) 12.5 microM. Interestingly, the corresponding mono-ester derivatives of 3 showed no such selectivity.

Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release

Publisher: Springer Science and Business Media LLC

Date: 05-05-2015

DOI: 10.1038/MP.2015.56

Abstract: Hormones and neurotransmitters are stored in specialised vesicles and released from excitable cells through exocytosis. During vesicle fusion with the plasma membrane, a transient fusion pore is created that enables transmitter release. The protein dynamin is known to regulate fusion pore expansion (FPE). The mechanism is unknown, but requires its oligomerisation-stimulated GTPase activity. We used a palette of small molecule dynamin modulators to reveal bi-directional regulation of FPE by dynamin and vesicle release in chromaffin cells. The dynamin inhibitors Dynole 34-2 and Dyngo 4a and the dynamin activator Ryngo 1-23 reduced or increased catecholamine released from single vesicles, respectively. Total internal reflection fluorescence (TIRF) microscopy demonstrated that dynamin stimulation with Ryngo 1-23 reduced the number of neuropeptide Y (NPY) kiss-and-run events, but not full fusion events, and slowed full fusion release kinetics. Amperometric stand-alone foot signals, representing transient kiss-and-run events, were less frequent but were of longer duration, similarly to full erometric spikes and pre-spike foot signals. These effects are not due to alterations in vesicle size. Ryngo 1-23 action was blocked by inhibitors of actin polymerisation or myosin II. Therefore, we demonstrate using a novel pharmacological approach that dynamin not only controls FPE during exocytosis, but is a bi-directional modulator of the fusion pore that increases or decreases the amount released from a vesicle during exocytosis if it is activated or inhibited, respectively. As such, dynamin has the ability to exquisitely fine-tune transmitter release.

Modified norcantharidins

Publisher: Elsevier BV

Date: 04-2004

DOI: 10.1016/J.BMCL.2004.01.093

Glycogen synthase kinase 3 regulates acrosomal exocytosis in mouse spermatozoa via dynamin phosphorylation

Publisher: Wiley

Date: 25-03-2015

DOI: 10.1096/FJ.14-265553

Abstract: The dynamin family of GTPases has been implicated as novel regulators of the acrosome reaction, a unique exocytotic event that is essential for fertilization. Dynamin activity during the acrosome reaction is accompanied by phosphorylation of key serine residues. We now tested the hypothesis that glycogen synthase kinase 3 (GSK3) is the protein kinase responsible for dynamin phosphorylation at these phosphosites in mouse spermatozoa. Pharmacologic inhibition of GSK3 in mature mouse spermatozoa (CHIR99021: IC50 = 6.7 nM) led to a significant reduction in dynamin phosphorylation (10.3% vs. 27.3% P < 0.001), acrosomal exocytosis (9.7% vs. 25.7% P < 0.01), and in vitro fertilization (53% vs. 100% P < 0.01). GSK3 was shown to be present in developing germ cells where it colocalized with dynamin in the peri-acrosomal domain. However, additional GSK3 was acquired by maturing mouse spermatozoa within the male reproductive tract, via a novel mechanism involving direct interaction of sperm heads with extracellular structures known as epididymal dense bodies. These data reveal a novel mode for the cellular acquisition of a protein kinase and identify a key role for GSK3 in the regulation of sperm maturation and acrosomal exocytosis.

Inhibition of dynamin by dynole 34-2 induces cell death following cytokinesis failure in cancer cells.

Publisher: American Association for Cancer Research (AACR)

Date: 09-2011

DOI: 10.1158/1535-7163.MCT-11-0067

Abstract: Inhibitors of mitotic proteins such as Aurora kinase and polo-like kinase have shown promise in preclinical or early clinical development for cancer treatment. We have reported that the MiTMAB class of dynamin small molecule inhibitors are new antimitotic agents with a novel mechanism of action, blocking cytokinesis. Here, we examined 5 of the most potent of a new series of dynamin GTPase inhibitors called dynoles. They all induced cytokinesis failure at the point of abscission, consistent with inhibition of dynamin while not affecting other cell cycle stages. All 5 dynoles inhibited cell proliferation (MTT and colony formation assays) in 11 cancer cell lines. The most potent GTPase inhibitor, dynole 34-2, also induced apoptosis, as revealed by cell blebbing, DNA fragmentation, and PARP cleavage. Cell death was induced specifically following cytokinesis failure, suggesting that dynole 34-2 selectively targets iding cells. Dividing HeLa cells were more sensitive to the antiproliferative properties of all 5 dynoles compared with non iding cells, and nontumorigenic fibroblasts were less sensitive to cell death induced by dynole 34-2. Thus, the dynoles are a second class of dynamin GTPase inhibitors, with dynole 34-2 as the lead compound, that are novel antimitotic compounds acting specifically at the abscission stage. Mol Cancer Ther 10(9) 1553–62. ©2011 AACR.

Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents

Publisher: Wiley

Date: 10-11-2022

DOI: 10.1002/CMDC.202100560

Abstract: Five focused libraries of pyrimidine‐based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad‐spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono‐substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di‐ and tri‐ substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1–10, 10–25 and 25–60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF‐7 (breast), BE2‐C (glioblastoma), SJ‐G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues ( 31 a , b ) developed returned average GI 50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N 2 ‐(3‐dimethylaminopropyl)‐ N 4 ‐dodecyl‐6‐methylpyrimidine‐2,4‐diamine ( 31 a ) and N 4 ‐(3‐dimethylaminopropyl)‐ N 2 ‐dodecyl‐6‐methylpyrimidine‐2,4‐diamine ( 31 b ).

Azido and Diazarinyl Analogues of Bis‐Tyrphostin as Asymmetrical Inhibitors of Dynamin GTPase

Publisher: Wiley

Date: 29-06-2009

DOI: 10.1002/CMDC.200900054

Abstract: Probing the dynamin binding site: Bis-tyrphostin (1, Bis-T), is a potent inhibitor of the phospholipid-stimulated GTPase activity of dynamin I. Analogues of Bis-T have significant potential as a biological probes for the dissection of endocytic pathways. Bis-T-derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues (23 and 24) represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibition.Two azidobenzyl amide (4 and 23) and one 3-trifluoromethyl-3H-diazirin-3-ylphenyl (24) analogues of bis-tyrphostin (1, Bis-T) were synthesised as potential photoaffinity labels for the elucidation of the binding site of compound 1 in dynamin I. Of the two azidobenzyl amide analogues (4 and 23), the terminally substituted 23 retained dynamin I GTPase inhibition (IC(50)=6.4+/-2.8 microM) whilst 4, which was substituted on the central carbon of the amide linker, displayed no activity. Analogue 24 also retained inhibitory activity (IC(50)=36+/-9 microM). Photoaffinity labelling experiments did not unequivocally elucidate the binding pocket of compound 1. However, compounds 23 and 24 represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibitory activity, providing a new direction for analogue synthesis.

Cytotoxic 1,2,3‐Triazoles as Potential Leads Targeting the S100A2‐p53 Complex: Synthesis and Cytotoxicity

Publisher: Wiley

Date: 12-07-2021

DOI: 10.1002/CMDC.202000950

Abstract: In silico screening predicted 1 ( N ‐(4‐((4‐(3‐(4‐(3‐methoxyphenyl)‐1 H ‐1,2,3‐triazol‐1‐yl)propyl)piperazin‐1‐yl) sulfonyl)‐phenyl)acetamide) as an inhibitor of the S100A2‐p53 protein‐protein interaction. S100A2 is a validated pancreatic cancer drug target. In the MiaPaCa‐2 pancreatic cell line, 1 was a ∼50 μM growth inhibitor. Synthesis of five focused compound libraries and cytotoxicity screening revealed increased activity from the presence of electron withdrawing moieties on the sulfonamide aromatic ring, with the 3,5‐bis‐CF 3 Library 3 analogues the most active, with GI 50 values of 0.91 (3‐ClPh 13 i BxPC‐3, Pancreas) to 9.0 μM (4‐CH 3 13 d PANC‐1, Pancreas). Activity was retained against an expanded pancreatic cancer cell line panel (MiaPaCa‐2, BxPC‐3, AsPC‐1, Capan‐2, PANC‐1 and HPAC) and the normal cell line MCF10A (breast). Bulky 4‐disposed substituents on the terminal phenyl ring enhanced broad spectrum activity with growth inhibition values spanning 1.1 to 3.1 μM (4‐C(CH 3 ) 3 13 e BxPC‐3 and AsPC‐1 (pancreas), respectively). Central alkyl spacer contraction from propyl to ethyl proved detrimental to activity with Library 4 and 5.5‐ to 10‐fold less cytotoxic than the propyl linked Library 2 and Library 3 . The data herein was consistent with the predicted binding poses of the compounds evaluated. The highest levels of cytotoxicity were observed with those analogues best capable of adopting a near identical pose to the p53‐peptide in the S100A2‐p53 binding groove.

Developmental expression of the dynamin family of mechanoenzymes in the mouse epididymis

Publisher: Oxford University Press (OUP)

Date: 20-12-2016

DOI: 10.1095/BIOLREPROD.116.145433

Abstract: The mammalian epididymis is an exceptionally long ductal system tasked with the provision of one of the most complex intraluminal fluids found in any exocrine gland. This specialized milieu is continuously modified by the combined secretory and absorptive of the surrounding epithelium and thus finely tuned for its essential roles in promoting sperm maturation and storage. While considerable effort has been focused on defining the composition of the epididymal fluid, relatively less is known about the intracellular trafficking machinery that regulates this luminal environment. Here, we characterize the ontogeny of expression of a master regulator of this machinery, the dynamin family of mechanoenzymes. Our data show that canonical dynamin isoforms were abundantly expressed in the juvenile mouse epididymis. However, in peripubertal and adult animals dynamin takes on a heterogeneous pattern of expression such that the different isoforms displayed both cell- and segment-specific localization. Thus, dynamin 1 and 3 were predominately localized in the distal epididymal segments (corpus and cauda), where they were found within clear and principal cells, respectively. In contrast, dynamin 2 was expressed throughout the epididymis, but localized to the Golgi apparatus of the principal cells in the proximal (caput) segment and the luminal border of these cells in more distal segments. These dynamin isoforms are therefore ideally positioned to play complementary, nonredundant roles in the regulation of the epididymal milieu. In support of this hypothesis, selective inhibition of dynamin altered the profile of proteins secreted from an immortalized caput epididymal cell line.

Development of Second-Generation Indole-Based Dynamin GTPase Inhibitors

Publisher: American Chemical Society (ACS)

Date: 18-12-2012

DOI: 10.1021/JM300844M

Abstract: Focused library development of our lead 2-cyano-3-(1-(3-(dimethylamino)propyl)-2-methyl-1H-indol-3-yl)-N-octylacrylamide (2) confirmed the tertiary dimethylamino-propyl moiety as critical for inhibition of dynamin GTPase. The cyanoamide moiety could be replaced with a thiazole-4(5H)-one isostere (19, IC(₅₀(dyn I)) = 7.7 μM), reduced under flow chemistry conditions (20, IC(₅₀(dyn I)) = 5.2 μM) or replaced by a simple amine. The latter provided a basis for a high yield library of compounds via a reductive amination by flow hydrogenation. Two compounds, 24 (IC(₅₀ (dyn I)) = 0.56 μM) and 25 (IC(₅₀(dyn I)) = 0.76 μM), stood out. Indole 24 is nontoxic and showed increased potency against dynamin I and II in vitro and in cells (IC(₅₀(CME)) = 1.9 μM). It also showed 4.4-fold selectivity for dynamin I. The indole 24 compound has improved isoform selectivity and is the most active in-cell inhibitor of clathrin-mediated endocytosis reported to date.

Dynamin regulates specific membrane fusion events necessary for acrosomal exocytosis in mouse spermatozoa

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1074/JBC.M112.392803

Molecularly Imprinted Polymers and Room Temperature Ionic Liquids: Impact of Template on Polymer Morphology

Publisher: CSIRO Publishing

Date: 2007

DOI: 10.1071/CH06284

Abstract: Molecularly imprinted polymers (MIPs) were generated for trans-aconitic acid 1 and cocaine 2 in a variety of porogens (CH3CN, CHCl3, [bmim][BF4], and [bmim][PF6]). MIP synthesis in either [bmim][BF4] or [bmim][PF6] resulted in significant acceleration of polymerization rates and, in the case of low temperature polymerizations, reactions were complete in less than 2 h, while no product was observed in the corresponding volatile organic carbon (VOC) porogen. In all instances, MIPs generated in [bmim][BF4] or [bmim][PF6] returned imprinting selectivities (I values) on par with or better than the corresponding MIP generated in VOCs. Imprinting values ranged between I = 1 and 2.9, with rebinding limited to 1 h. MIP synthesis conducted at low temperature (5°C) afforded the highest I values. Scanning electron microscopy examination of MIP morphology highlighted an unexpected template effect with MIP structure varying between discrete nanoparticles and robust monoliths. This template–monomer interaction was also observed in the rates of polymerizations with differences noted in reaction times for 1 and 2 MIPs, thus providing indirect conformation of our previously proposed use of molecular modelling–nuclear magnetic resonance titrations (the MM-NMR method) in the design phase of MIP generation. In addition, considerable batch-to-batch rebinding selectivities were observed.

Wiskostatin and other carbazole scaffolds as off target inhibitors of dynamin I GTPase activity and endocytosis

Publisher: Elsevier BV

Date: 02-2023

DOI: 10.1016/J.EJMECH.2022.115001

The dynamin inhibitors MiTMAB and OcTMAB induce cytokinesis failure and inhibit cell proliferation in human cancer cells.

Publisher: American Association for Cancer Research (AACR)

Date: 07-2010

DOI: 10.1158/1535-7163.MCT-10-0161

Abstract: The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer. Mol Cancer Ther 9(7) 1995–2006. ©2010 AACR.

1,8-Naphthalimide derivatives: New leads against dynamin i GTPase activity

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5OB00751H

Abstract: Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI.

A Direct Fluorescent Activity Assay for Glycosyltransferases Enables Convenient High‐Throughput Screening: Application to O‐GlcNAc Transferase

Publisher: Wiley

Date: 02-04-2020

DOI: 10.1002/ANIE.202000621

FD5180, a Novel Protein Kinase Affinity Probe, and the Effect of Bead Loading on Protein Kinase Identification

Publisher: American Chemical Society (ACS)

Date: 25-07-2017

DOI: 10.1021/ACSOMEGA.7B00020

Small Molecule Inhibitors of Dynamin I GTPase Activity:  Development of Dimeric Tyrphostins

Publisher: American Chemical Society (ACS)

Date: 29-10-2005

DOI: 10.1021/JM040208L

Abstract: Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a microM potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 microM). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low microM potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50= 5.1 +/- 0.6 microM), its 3,4,5-trihydroxy congener (10) (IC50= 1.7 +/- 0.2 microM), and the corresponding 3-methyl ether (11) (IC50= 9 +/- 3 microM). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50's of 1.7 +/- 0.2, 1.7 +/- 0.2, and 5 +/- 1 microM, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50's of 42 +/- 3, 38 +/- 2, and 61 +/- 2 microM, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.

A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone

Publisher: The Royal Society

Date: 04-2018

DOI: 10.1098/RSOS.171189

Abstract: Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library A , were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI 50 ) values of 4–12 µM only the 3,4-dimethoxyphenyl 23 and 3-biphenyl 28 variants were broad-spectrum active—HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma). Library B with a second aryl moiety exhibited broad-spectrum cytotoxicity with MCF-7 cells’ GI 50 values of 5.6 ± 0.7 and 5.1 ± 0.5 µM for 2,5-dimethoxy-3-(naphthalene-1-yl)-6-(naphthalene-3-yl) 33 and 2,5-dimethoxy-3-(biaryl-2-yl)-6-(naphthalene-3-yl) 36, respectively. Similar potencies were also noted with 2,5-dimethoxy-3,6-diphenyl 30 against A2780 (GI 50 = 5.9 ± 0.0 µM) and with 2,5-dimethoxy-3-(biaryl-3-yl)-6-(naphthalene-3-yl) 37 against HT29 (GI 50 = 5.4 ± 0.4 µM), while the 3,4-dimethoxy mono-aryl analogue 23 exhibited good levels of activity against A2780 (GI 50 = 3.8 ± 0.75 µM), the neuroblastoma cell line BE2-C (GI 50 = 3 ± 0.35 µM) and SMA (GI 50 = 3.9 ± 0.54 µM). Introduction of the amino-substituted Library C gave 2-(naphthalen-1-yl)-5-(naphthalen-3-yl)-3,6-bis(propylamino) 43, with excellent activity against HT29 (0.08 ± 0.0 µM), MCF-7 (0.17 ± 0.1 µM), A2780 (0.14 ± 0.1 µM), A431 (0.11 ± 0.0 µM), Du145 (0.16 ± 0.1 µM), BE2-C (0.08 ± 0.0 µM) and MIA (0.1 ± 0.0 µM).

Formulation of Cocaine-Imprinted Polymers Utilizing Molecular Modelling and NMR Analysis

Publisher: CSIRO Publishing

Date: 2005

DOI: 10.1071/CH04138

Abstract: Molecular imprinted polymers (MIPs) have distinctive features that make them attractive as an inexpensive, reusable, and robust field-based detection system for illicit substances. Optimizing MIP performance is traditionally attained by the synthesis and evaluation of a plethora of in idual formulations. A non-covalently imprinted polymer for cocaine has been prepared using a commercially available molecular modelling package (Spartan 02) to predict energetically favourable monomer–template interactions between the target (T) and two different functional monomers (FM)—methacrylic acid (MAA) and 4-vinylpyridine (4VP). NMR studies undertaken to assess target–monomer behaviour in solution were in good agreement with the computational data. MIPs involving three target-to-functional monomer ratios (1 : 2, 1 : 6, and 1 : 14) were prepared and evaluated. Target rebinding was found to be most favourable in the 1 : 2 formulation with a target-selective binding of 0.48 ppm and an imprinting factor (I) of 2.8 obtained for 10 mg of test polymer.

Norcantharimide analogues possessing terminal phosphate esters and their anti-cancer activity

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.BMC.2011.01.031

Abstract: A family of norcantharidin analogues possessing a terminal alcohol (ethanol, propanol, butanol, pentanol, hexanol and cyclohexanol) moiety were treated with either chlorodiethyl, chlorodiphenyl or chloro-bis-trichloroethyl-phosphate to afford highly focused libraries of the corresponding phosphate esters. Subsequent biological screening against a panel of nine human cancer cell lines identified a trend between the ease of phosphate unmasking (phosphate ester hydrolysis) and cell death. The most potent analogues possessed either a diphenyl or a bis-trichloroethyl moiety. The effect of alkyl spacer was also examined with the hexyl analogues typically more potent. 4-Aza-4-(3-{bis(2,2,2-trichloroethyl)phosphate}propyl)-10-oxatricyclo[5.2.1.0]decane-3,5-dione (10b) was the most potent analogue synthesised with an average GI(50) of 11 μM across a panel of nine human carcinoma cell lines: colon carcinoma (HT29 and SW480) breast carcinoma (MCF-7) ovarian carcinoma (A2780) lung carcinoma (H460) skin carcinoma (A431) prostate carcinoma (DU145) neuronal carcinoma (BE2-C) and brain carcinoma (SJ-G2). This represents a fivefold improvement in anti-proliferative activity relative to the lead, norcantharidin.

Potentiometric determination of acid dissociation constants of novel biaryl monomers

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5AY01673H

Abstract: p K a s of novel biaryl monomers for MIPs designed for aqueous environment were determined by the Yasuda–Shedlovsky method.

Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs)

Publisher: Royal Society of Chemistry (RSC)

Date: 2022

DOI: 10.1039/D2CC03092F

Abstract: A new class of arylazopyrazole photoswitchable PROTACs (AP-PROTACs) enables light-triggered degradation of a specific ensemble of protein kinases.

Inhibition of protein phosphatase 2A by cantharidin analogues

Publisher: Elsevier BV

Date: 05-1996

DOI: 10.1016/0960-894X(96)00166-7

The synthesis and biological activity of novel anthracenone-pyranones and anthracenone-furans.

Publisher: Elsevier BV

Date: 07-2015

DOI: 10.1016/J.BMC.2015.04.032

Abstract: An efficient and ergent methodology for the synthesis of new anthracenone-pyranones and anthracenone-furans is described. Key reactions discussed in these syntheses include an aldehyde promoted annulation with a β-keto-sulfoxide, a domino alkyne insertion/carbonylation/Nu-acylation and a DMEDA promoted Castro-Stephens reaction. We also report the in vitro growth inhibition of these compounds in a range of human cancer cells. The natural product BE-26554A displayed good cell growth activity on BE2-C neuroblastoma and SMA glioblastoma cell lines at 0.17 and 0.16μM (GI50), respectively. Of note, were a CF3 functionalised anthracenone 4-pyranone (chromone) derivative 22, and an anthracenone-furan derivative 54 which displayed 0.20μM and 0.38μM growth inhibition, respectively, in the BE2-C neuroblastoma cell line.

Dynamin Inhibition Blocks Botulinum Neurotoxin Type A Endocytosis in Neurons and Delays Botulism

Publisher: Elsevier BV

Date: 10-2011

DOI: 10.1074/JBC.M111.283879

(Z)-2-(3,4-Dichlorophenyl)-3-(1H-Pyrrol-2-yl)Acrylonitrile Exhibits Selective Antitumor Activity in Breast Cancer Cell Lines via the Aryl Hydrocarbon Receptor Pathway.

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 21-12-2018

DOI: 10.1124/MOL.117.109827

Abstract: We have previously reported the synthesis and breast cancer selectivity of (

Damaging legacy: maternal cigarette smoking has long-term consequences for male offspring fertility

Publisher: Oxford University Press (OUP)

Date: 30-09-2014

DOI: 10.1093/HUMREP/DEU235

Abstract: What are the effects on fertility of cigarette smoke-induced toxicity on male offspring exposed during the gestational/weaning period? Maternal cigarette smoke exposure during the gestational/weaning period causes long-term defects in male offspring fertility. Cigarette smoke is a well-known reproductive toxicant which is particularly harmful to both fetal and neonatal germ cells. However, recent studies suggest a significant portion of young mothers in the developed world still smoke during pregnancy. In the context of male reproductive health, our understanding of the effects of in utero exposure on offspring fertility is limited. In this study, 27 C57BL/6 5-week-old female mice were exposed via the nose-only to cigarette smoke (treatment) or 27 were exposed to room air (control) for 6 weeks before being housed with stud males to produce litters. In the treatment group, smoke exposure continued throughout mating, pregnancy and lactation until weaning of pups at 21 days post birth. Male offspring were examined at post-natal days 3, 6, 12, 21 and 98 (adult). Approximately 108 maternal smoke-exposed C57BL/6 offspring and controls were examined. Spermatogenesis was examined using testicular histology and apoptosis/DNA damage was assessed using caspase immunohistochemistry and TUNEL. Sertoli cell morphology and fluctuations in the spermatogonial stem cell population were also examined using immunohistochemistry. Microarray and QPCR analysis were performed on adult testes to examine specific long-term transcriptomic alteration as a consequence of maternal smoke exposure. Sperm counts and motility, zona/oolemma binding assays, COMET analysis and mitochondrial genomic sequencing were also performed on spermatozoa obtained from adult treated and control mice. Fertility trials using exposed adult male offspring were also performed. Maternal cigarette smoke exposure caused increased gonocyte and meiotic spermatocyte apoptosis (P < 0.01) as well as germ cell depletion in the seminiferous tubules of neonatal and juvenile offspring. Aberrant testicular development characterized by abnormal Sertoli and germ cell organization, a depleted spermatogonial stem cell population (P < 0.01), atrophic seminiferous tubules and increased germ cell DNA damage (P < 0.01) persisted in adult offspring 11 weeks after exposure. Microarray analysis of adult offspring testes associated these defects with meiotic germ cell development, sex hormone metabolism, oxidative stress and Sertoli cell signalling. Next generation sequencing also revealed a high mitochondrial DNA mutational load in the testes of adult offspring (P < 0.01). Adult maternal smoke-exposed offspring also had reduced sperm counts with spermatozoa exhibiting morphological abnormalities (P < 0.01), affecting motility and fertilization potential. Odf2, a spermatozoa flagellum component required for coordinated ciliary beating, was also significantly down-regulated (P < 0.01) in maternal smoke-exposed adult offspring, with aberrant localization along the spermatozoa flagellum. Adult maternal smoke-exposed offspring took significantly longer to impregnate control females and had a slight but significant (P < 0.01) reduction in litter size. This study examined only one species (mouse) using a smoking model which only simulates human cigarette smoke exposure. This study represents the first comprehensive animal model of maternal smoking on male offspring reproductive function, suggesting that exposure during the gestational/weaning period causes long-term defects in male offspring fertility. This is due to a compromised spermatogonial stem cell population resulting from gonocyte apoptosis and impaired spermatogenic development. This results in significant germ cell damage and Sertoli cell dysfunction, impacting germ cell number, tubule organization, DNA damage and spermatozoa in adult offspring. This study strengthens the current literature suggesting that maternal exposure impairs male offspring fertility, which is currently debated due to conflicting studies. This study was funded by the Australian Research Council, Hunter Medical Research Institute, National Health and Medical Research Council of Australia and the Newcastle Permanent Building Society Charitable Trust. The authors declare no conflict of interest.

Serine−Threonine Protein Phosphatase Inhibitors:  Development of Potential Therapeutic Strategies

Publisher: American Chemical Society (ACS)

Date: 19-02-2002

DOI: 10.1021/JM010066K

Norcantharidin analogues with nematocidal activity in Haemonchus contortus.

Publisher: Elsevier BV

Date: 06-2011

DOI: 10.1016/J.BMCL.2011.04.031

Abstract: With the major problems with resistance in parasitic nematodes of livestock to anthelmintic drugs, there is an urgent need to develop new nematocides. In the present study, we employed a targeted approach for the design of a series of norcantharidin analogues (n=54) for activity testing against the barber's pole worm (Haemonchus contortus) of small ruminants in a larval development assay (LDA) and also for toxicity testing on nine distinct human cell lines. Although none of the 54 analogues synthesized were toxic to any of these cell lines, three of them (N-octyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B2), N-decyl-7-oxabicyclo(2.2.1)heptane-2,3-dicarboximide (B3) and 4-[(4-methyl)-3-ethyl-2-methyl-5-phenylfuran-10-oxa-4-azatricyclo[5.2.1]decane-3,5-dione (B21) reproducibly displayed 99-100% lethality to H. contortus in LDA, with LD(50s) of 25-40 μM. The high 'hit rate' (5.6%) indicates that the approach taken here has advantages over conventional drug screening methods. A major advantage of norcantharidin analogues over some other currently available anthelmintics is that they can be produced in one to two steps in large amounts at low cost and high purity, and do not require any additional steps for the isolation of the active isomer. This positions them well for commercial development.

Small-Molecule Inhibitors of the NusB–NusE Protein–Protein Interaction with Antibiotic Activity

Publisher: American Chemical Society (ACS)

Date: 25-07-2017

DOI: 10.1021/ACSOMEGA.7B00273

A Direct Fluorescent Activity Assay for Glycosyltransferases Enables Convenient High‐Throughput Screening: Application to O‐GlcNAc Transferase

Publisher: Wiley

Date: 02-04-2020

DOI: 10.1002/ANGE.202000621

Indium-Mediated Addition of 4-Bromocrotonic Acid to Aldehydes and Ketones—A Simple, High Yielding Route to α-Allyl-β-Hydroxy Carboxylic Acids

Publisher: CSIRO Publishing

Date: 2004

DOI: 10.1071/CH03212

Abstract: We report a simple procedure for the indium-mediated addition of 4-bromocrotonic acid to a variety of aldehydes and ketones. In all instances the reaction proceeds exclusively with α-addition and typically in moderate to good yields (42–100%). The effect of solvent is minimal allowing a wide choice of conditions (methanol, ethanol, ethanol/water, water, tetrahydrofuran, and the ionic liquid [bmIm][BF4]).

The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening

Publisher: American Chemical Society (ACS)

Date: 24-06-2010

DOI: 10.1021/JM100442U

Abstract: We report the development of a homology model for the GTP binding domain of human dynamin I based on the corresponding crystal structure of Dictyostelium discoidum dynamin A. Virtual screening identified 2-[(2-biphenyl-2-yl-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonyl)amino]-4-chlorobenzoic acid (1) as a approximately 170 microM potent inhibitor. Homology modeling- and focused library-led synthesis resulted in development of a series of active compounds (the "pthaladyns") with 4-chloro-2-(2-(4-(hydroxymethyl)phenyl)-1,3-dioxoisoindoline-5-carboxamido)benzoic acid (29), a 4.58 +/- 0.06 microM dynamin I GTPase inhibitor. Pthaladyn-29 displays borderline selectivity for dynamin I relative to dynamin II ( approximately 5-10 fold). Only pthaladyn-23 (dynamin I IC(50) 17.4 +/- 5.8 microM) was an effective inhibitor of dynamin I mediated synaptic vesicle endocytosis in brain synaptosomes with an IC(50) of 12.9 +/- 5.9 microM. This compound was also competitive with respect to Mg(2+).GTP. Thus the pthaladyns are the first GTP competitive inhibitors of dynamin I and II GTPase and may be effective new tools for the study of neuronal endocytosis.

Efficient preparation and improved sensitivity of molecularly imprinted polymers using room temperature ionic liquids

Publisher: Royal Society of Chemistry (RSC)

Date: 2006

DOI: 10.1039/B517886J

Abstract: Synthesis of trans-aconitic acid molecularly imprinted polymers in [bmim][BF4] and [bmim][PF6] under photochemical (5 degrees C, AIBN) and thermal (60 degrees C, AIBN) conditions gave polymer micro-spheres (<200 nm), under bulk and precipitation polymerisation conditions, and higher selectivity indices (100% improvement) relative to the more traditional precipitation polymerisation (CH3CN, high solvent volumes) approach.

Parallel Solution-Phase Synthesis of Targeted Tyrphostin Libraries with Anticancer Activity

Publisher: CSIRO Publishing

Date: 2005

DOI: 10.1071/CH04143

Abstract: The combination of semi-automation, an elegant synthesis, and parallel solution-phase synthesis approaches has allowed the development of five targeted, symmetrical tyrphostin compound libraries. These libraries on average are comprised of 12 compounds. Notwithstanding this, low micromolar potent growth inhibitors against HT29 (colorectal carcinoma) and G401 (renal carcinoma) cell lines were discovered. Additionally, significant SAR data was obtained. We noted that the most potent growth inhibitory activity was consistently observed for those analogues that possessed a 2-chlorophenyl (for 10: GI50 HT29 5.5 ± 0.4 μM, GI50 G401 2.6 ± 0.4 μM for 23: GI50 HT29 2.4 ± 0.2 μM, GI50 G401 1.9 ± 1 μM for 34: GI50 HT29 8.8 ± 3.1 μM, GI50 G401 6.2 ± 2.9 μM for 46: GI50 HT29 5.2 ± 0.9 μM, GI50 G401 3.7 ± 0.6 μM for 57: GI50 HT29 4.6 ± 0.8 μM, GI50 G401 2.1 ± 0.2 μM), a 3-chlorophenyl (for 11: GI50 HT29 3.8 ± 0.7 μM, GI50 G401 1.7 ± 0.7 μM for 48: GI50 HT29 5.9 ± 0.1 μM, GI50 G401 3.4 ± 0.6 μM for 58: GI50 HT29 4.8 ± 0.9 μM, GI50 G401 3.4 ± 0.2 μM), or a 3-methoxyphenyl substituent (for 13: GI50 HT29 7.4 ± 3.8 μM, GI50 G401 2.8 ± 0.5 μM for 26: GI50 HT29 4.5 ± 0.5 μM, GI50 G401 4.9 ± 1 μM for 37: GI50 HT29 3.7 ± 0.2 μM, GI50 G401 1.6 ± 0.2 μM for 49: GI50 HT29 3.7 ± 0.4 μM, GI50 G401 3.4 ± 0.2 μM for 60: GI50 HT29 4.1 ± 0.6 μM, GI50 G401 1.8 ± 0.3 μM). Finally, we noted that increasing the distance between the terminal aromatic rings had only a minimal effect on the 2-, 3-chlorophenyl, and 3-methoxyphenyl analogues, but did have a favourable effect on OH, COOH, and multiply substituted analogues.

Serine/threonine phosphatases in socioeconomically important parasitic nematodes—Prospects as novel drug targets?

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.BIOTECHADV.2010.08.008

Abstract: Little is known about the fundamental biology of parasitic nematodes (=roundworms) that cause serious diseases, affecting literally billions of animals and humans worldwide. Unlocking the biology of these neglected pathogens using modern technologies will yield crucial and profound knowledge of their molecular biology, and could lead to new treatment and control strategies. Supported by studies in the free-living nematode, Caenorhabditis elegans, some recent investigations have provided improved insights into selected protein phosphatases (PPs) of economically important parasitic nematodes (Strongylida). In the present article, we review this progress and assess the potential of serine/threonine phosphatase (STP) genes and/or their products as targets for new nematocidal drugs. Current information indicates that some small molecules, known to specifically inhibit PPs, might be developed as nematocides. For instance, some cantharidin analogues are known to display exquisite PP-inhibitor activity, which indicates that some of them could be designed and tailored to specifically inhibit selected STPs of nematodes. This information provides prospects for the discovery of an entirely novel class of nematocides, which is of paramount importance, given the serious problems linked to anthelmintic resistance in parasitic nematode populations of livestock, and has the potential to lead to significant biotechnological outcomes.

The antiplasmodial activity of norcantharidin analogs

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/J.BMCL.2010.09.004

Abstract: The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 μM against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50)=3.0±0.0 and W2 IC(50)=3.0±0.8 μM) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6=8.9±0.9 and W2 IC(50)=12.5±2.2 μM, representing a fivefold enhancement over norcantharidin.

Dynamin 2 is essential for mammalian spermatogenesis

Publisher: Springer Science and Business Media LLC

Date: 11-10-2016

DOI: 10.1038/SREP35084

Abstract: The dynamin family of proteins play important regulatory roles in membrane remodelling and endocytosis, especially within brain and neuronal tissues. In the context of reproduction, dynamin 1 (DNM1) and dynamin 2 (DNM2) have recently been shown to act as key mediators of sperm acrosome formation and function. However, little is known about the roles that these proteins play in the developing testicular germ cells. In this study, we employed a DNM2 germ cell-specific knockout model to investigate the role of DNM2 in spermatogenesis. We demonstrate that ablation of DNM2 in early spermatogenesis results in germ cell arrest during prophase I of meiosis, subsequent loss of all post-meiotic germ cells and concomitant sterility. These effects become exacerbated with age, and ultimately result in the demise of the spermatogonial stem cells and a Sertoli cell only phenotype. We also demonstrate that DNM2 activity may be temporally regulated by phosphorylation of DNM2 via the kinase CDK1 in spermatogonia, and dephosphorylation by phosphatase PPP3CA during meiotic and post-meiotic spermatogenesis.

Synthesis, molecular modeling and biological activity of methyl and thiomethyl substituted pyrimidines as corticotropin releasing hormone type 1 antagonists

Publisher: Royal Society of Chemistry (RSC)

Date: 2003

DOI: 10.1039/B305458F

Abstract: Four small, targeted libraries of differentially substituted amino pyrimidines were synthesized in moderate to good yields. Excellent regiochemistry was observed for substitution at C2/C4 with selectivity > 50:1 noted. All analogues were screened for their ability to interact with CRH1 and CRH2 receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH2. However, several compounds were potent and selective CRH1 antagonists, most notably 13a Ki = 39 nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH1 pharmacophore (J Med. Chem., 1999, 42, 2351-2357).

Synthesis and anticancer activity of a series of norcantharidin analogues

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/J.EJMECH.2012.06.010

Abstract: Cantharidin (1) and norcantharidin (2) display high levels of anticancer activity against a broad range of tumour cell lines. Synthetic manipulation of norcantharidin yields (3S,3aR,4S,7R,7aS)-3-hydroxyhexahydro-4,7-epoxyisobenzofuran-1(3H)-one (3), which also displays a high level of anticancer activity against tumour cells but interestingly, shows selectivity towards HT29 (colon GI(50) = 14 μM) and SJ-G2 (glioblastoma GI(50) = 15 μM) cell lines. Substitution at the hydroxyl group of the cyclic lactone within (3) produces a diasteromeric pair of products that have no difference in cytotoxicity over the cell lines tested. Incorporation of an isopropyl tail at this position (16) produced the most promising compound of this series to date, with strong selectivity towards HT29 (colon GI(50) = 19 μM) and SJ-G2 (glioblastoma GI(50) = 21 μM) cell lines but completely void of any activity against the remaining tumour cell lines (GI(50) > 100 μM), as per the parent molecule. We also discovered that the introduction of a terminal phosphate moiety (28) at the same position produced a different trend in cytotoxicity with strong activity in BE2-C (neuroblastoma GI(50) = 9 μM) cells suggestive of an alternate mode of action.

Amino alcohol acrylonitriles as broad spectrum and tumour selective cytotoxic agents

Publisher: Royal Society of Chemistry (RSC)

Date: 2021

DOI: 10.1039/D1MD00021G

Abstract: We have identified specific dichlorophenylacrylonitriles as lead compounds in the development of novel anticancer drugs, notably, ( Z )- N -(4-(2-cyano-2-(3,4-dichlorophenyl)vinyl)phenyl)acetamide ( 1 ) and ANI-7 ( 2 ).

Expanding the utility of flow hydrogenation – a robust protocol restricting hydrodehalogenation

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C4RA09605C

Abstract: A commonly observed limitation of conducting hydrogenations under flow chemistry conditions is hydrodehalogenation.

Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief

Publisher: American Association for the Advancement of Science (AAAS)

Date: 31-05-2017

DOI: 10.1126/SCITRANSLMED.AAL3447

Abstract: Therapeutic targeting of the neurokinin 1 receptor in endosomes provides efficacious and prolonged pain relief.

Chemoselective flow hydrogenation approaches to isoindole-7-carboxylic acids and 7-oxa-bicyclio[2.2.1]heptanes

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3RA47657J

Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition.

Publisher: Wiley

Date: 08-12-2008

DOI: 10.1002/CMDC.200800192

Abstract: Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC(50) values of approximately 15 and approximately 3 mum, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC(50) values in the range of 15-10 microM (PP1) and 11-5 microM (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.

An efficient continuous flow approach to furnish furan-based biaryls

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C4OB01641F

Abstract: Suzuki cross-couplings of 5-formyl-2-furanylboronic acid with activated or neutral aryl bromides were performed under continuous flow conditions in the presence of (Bu) 4 N + F − and the immobilised t -butyl based palladium catalyst CatCart™ FC1032™.

Clathrin Terminal Domain-Ligand Interactions Regulate Sorting of Mannose 6-Phosphate Receptors Mediated by AP-1 and GGA Adaptors

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1074/JBC.M113.535211

Simian Hemorrhagic Fever Virus Cell Entry Is Dependent on CD163 and Uses a Clathrin-Mediated Endocytosis-Like Pathway

Publisher: American Society for Microbiology

Date: 2015

DOI: 10.1128/JVI.02697-14

Abstract: Simian hemorrhagic fever virus (SHFV) causes a severe and almost uniformly fatal viral hemorrhagic fever in Asian macaques but is thought to be nonpathogenic for humans. To date, the SHFV life cycle is almost completely uncharacterized on the molecular level. Here, we describe the first steps of the SHFV life cycle. Our experiments indicate that SHFV enters target cells by low-pH-dependent endocytosis. Dynamin inhibitors, chlorpromazine, methyl-β-cyclodextrin, chloroquine, and concanamycin A dramatically reduced SHFV entry efficiency, whereas the macropinocytosis inhibitors EIPA, blebbistatin, and wortmannin and the caveolin-mediated endocytosis inhibitors nystatin and filipin III had no effect. Furthermore, overexpression and knockout study and electron microscopy results indicate that SHFV entry occurs by a dynamin-dependent clathrin-mediated endocytosis-like pathway. Experiments utilizing latrunculin B, cytochalasin B, and cytochalasin D indicate that SHFV does not hijack the actin polymerization pathway. Treatment of target cells with proteases (proteinase K, papain, α-chymotrypsin, and trypsin) abrogated entry, indicating that the SHFV cell surface receptor is a protein. Phospholipases A2 and D had no effect on SHFV entry. Finally, treatment of cells with antibodies targeting CD163, a cell surface molecule identified as an entry factor for the SHFV-related porcine reproductive and respiratory syndrome virus, diminished SHFV replication, identifying CD163 as an important SHFV entry component. IMPORTANCE Simian hemorrhagic fever virus (SHFV) causes highly lethal disease in Asian macaques resembling human illness caused by Ebola or Lassa virus. However, little is known about SHFV's ecology and molecular biology and the mechanism by which it causes disease. The results of this study shed light on how SHFV enters its target cells. Using electron microscopy and inhibitors for various cellular pathways, we demonstrate that SHFV invades cells by low-pH-dependent, actin-independent endocytosis, likely with the help of a cellular surface protein.

Cantharimides: A new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A

Publisher: Elsevier BV

Date: 11-2001

DOI: 10.1016/S0960-894X(01)00594-7

Abstract: Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.

Steroids from an Australian sponge Psammoclema sp.

Publisher: American Chemical Society (ACS)

Date: 08-01-2009

DOI: 10.1021/NP800688F

Abstract: Investigation of an extract of the Australian marine sponge Psammoclema sp. for dynamin I inhibitory activity led to the isolation of four new trihydroxysterols (1-4) related to aragusterol G. These compounds were largely identified by 1D and 2D NMR spectroscopic methods. While 1 was found to be inactive in the dynamin bioassay, bioassays did reveal that compounds 1-4 inhibited the growth of colorectal, breast, ovarian, and prostate cancer cell lines (GI(50) 5-27 microM). The additional insight that these new compounds give to previous SAR studies is discussed briefly.

Protein Phosphatase Inhibition: Structure Based Design. Towards New Therapeutic Agents

Publisher: Bentham Science Publishers Ltd.

Date: 04-2004

DOI: 10.2174/1381612043452686

Abstract: Cellular signalling processes are governed by a delicate balance of phosphatase and kinase activity. Over the past few years there has been considerable effort directed toward the development of kinase based therapeutic agents, whilst phosphatase based therapeutics have lagged. Herein we address key issues relating to selected therapeutic targets: malignancy, diabetes, immunosuppression, cystic fibrosis, asthma and cardiovascular disease. As part of ongoing studies we examine the recent developments in understanding the key interactions between the okadaic acid class of compounds and the serine/threonine protein phosphatases 1, 2A and 2B. Crystal structure and molecular modelling guided inhibitor development is also a key focus of this article.

Cover Image, Volume 40, Issue 3

Publisher: Wiley

Date: 17-04-2020

DOI: 10.1002/MED.21610

Comparison of two transmission electron microscopy methods to visualize drug-induced alterations of gram-negative bacterial morphology

Publisher: MDPI AG

Date: 17-03-2021

DOI: 10.3390/ANTIBIOTICS10030307

Abstract: In this study, we optimized and compared different transmission electron microscopy (TEM) methods to visualize changes to Gram-negative bacterial morphology induced by treatment with a robenidine analogue (NCL195) and colistin combination. Aldehyde-fixed bacterial cells (untreated, treated with colistin or NCL195 + colistin) were prepared using conventional TEM methods and compared with ultrathin Tokuyasu cryo-sections. The results of this study indicate superiority of ultrathin cryo-sections in visualizing the membrane ultrastructure of Escherichia coli and Pseudomonas aeruginosa, with a clear delineation of the outer and inner membrane as well as the peptidoglycan layer. We suggest that the use of ultrathin cryo-sectioning can be used to better visualize and understand drug interaction mechanisms on the bacterial cell membrane.

An Ugi-intramolecular Diels–Alder route to highly substituted tetrahydroepoxyisoindole carboxamides

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.TET.2010.10.042

Synthesis and evaluation of novel ellipticines as potential anti-cancer agents.

Publisher: Royal Society of Chemistry (RSC)

Date: 2013

DOI: 10.1039/C2OB27186A

Abstract: Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 μM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 μM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11 GI(50) 1-18 μM) and in some cell lines better than Etoposide (VP-16 GI(50) = 0.04-5.2 μM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI(50) = 0.47-0.9 μM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI(50) values in the range of 1.3-28 μM.

Dynamin regulates L cell secretion in human gut

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.MCE.2021.111398

Abstract: The mechanochemical enzyme dynamin mediates endocytosis and regulates neuroendocrine cell exocytosis. Enteroendocrine L cells co-secrete the anorectic gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) postprandially and is a potential therapeutic target for metabolic diseases. In the present study, we aimed to determine if dynamin is implicated in human L cell secretion. Western blot was performed on the murine L cell line GLUTag. Static incubation of human colonic mucosae with activators and inhibitors of dynamin was carried out. GLP-1 and PYY contents of the secretion supernatants were assayed using ELISA. s: Both dynamin I and II are expressed in GLUTag cells. The dynamin activator Ryngo 1-23 evoked significant GLP-1 and PYY release from human colonic mucosae while the dynamin inhibitor Dynole 3-42 significantly inhibited release triggered by known L cell secretagogues. Thus, the cell signaling regulator dynamin is able to bi-directionally regulate L cell hormone secretion in the human gut and may represent a novel target for gastrointestinal-targeted metabolic drug development.

Identification and validation of small molecule modulators of the NusB-NusE interaction

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.BMCL.2016.11.091

Abstract: Formation of highly possessive antitermination complexes is crucial for the efficient transcription of stable RNA in all bacteria. A key step in the formation of these complexes is the protein-protein interaction (PPI) between N-utilisation substances (Nus) B and E and thus this PPI offers a novel target for a new antibiotic class. A pharmacophore developed via a secondary structure epitope approach was utilised to perform an in silico screen of the mini-Maybridge library (56,000 compounds) which identified 25 hits of which five compounds were synthetically tractable leads. Here we report the synthesis of these five leads and their biological evaluation as potential inhibitors of the NusB-NusE PPI. Two chemically erse scaffolds were identified to be low micro molar potent PPI inhibitors, with compound (4,6-bis(2',4',3.4 tetramethoxyphenyl))pyrimidine-2-sulphonamido-N-4-acetamide 1 and N,N'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 3 exhibiting IC

Cytotoxicity of a Series of Norcantharidin‐Inspired Tetrahydroepoxyisoindole Carboxamides

Publisher: Wiley

Date: 03-01-2017

DOI: 10.1002/CMDC.201600573

Abstract: A series of 28 norcantharidin (NorC)-inspired analogues were accessed via a robust two-step Ugi intramolecular Diels-Alder (IMDA) sequence. Four analogues displayed whole-cell cytotoxicity equipotent to that of NorC and cisplatin against a number of cancer cell lines and a normal breast cell line (MCF10A). Notably, (3S,3aS,6R)-2-benzyl-7-methyl-N-(naphthalen-2-yl)-1-oxo-1,2,3,6-tetrahydro-3a,6-epoxyisoindole-3-carboxamide (trans-27) displayed superior whole-cell activity against breast (MCF-7, GI

Development and interpretation of a QSAR model for in vitro breast cancer (MCF-7) cytotoxicity of 2-phenylacrylonitriles

Publisher: Springer Science and Business Media LLC

Date: 05-2021

DOI: 10.1007/S10822-021-00387-5

The solvent promoted addition of tetraallyltin to aldehydes: A convenient and chemoselective allylation procedure

Publisher: Elsevier BV

Date: 03-1996

DOI: 10.1016/0040-4039(96)00149-9

HIV infection is influenced by dynamin at 3 independent points in the viral life cycle

Publisher: Wiley

Date: 11-04-2017

DOI: 10.1111/TRA.12481

Abstract: CD4 T cells are important cellular targets for HIV-1, yet the primary site of HIV fusion remains unresolved. Candidate fusion sites are either the plasma membrane or from within endosomes. One area of investigation compounding the controversy of this field, is the role of the protein dynamin in the HIV life cycle. To understand the role of dynamin in primary CD4 T cells we combined dynamin inhibition with a series of complementary assays based on single particle tracking, HIV fusion, detection of HIV DNA products and active viral transcription. We identify 3 levels of dynamin influence on the HIV life cycle. Firstly, dynamin influences productive infection by preventing cell cycle progression. Secondly, dynamin influences endocytosis rates and increases the probability of endosomal fusion. Finally, we provide evidence in resting CD4 T cells that dynamin directly regulates the HIV fusion reaction at the plasma membrane. We confirm this latter observation using 2 ergent dynamin modulating compounds, one that enhances dynamin conformations associated with dynamin ring formation (ryngo-1-23) and the other that preferentially targets dynamin conformations that appear in helices (dyngo-4a). This in-depth understanding of dynamin's roles in HIV infection clarifies recent controversies and furthermore provides evidence for dynamin regulation specifically in the HIV fusion reaction.

Anhydride modified cantharidin analogues: synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity

Publisher: Elsevier BV

Date: 08-2000

DOI: 10.1016/S0960-894X(00)00323-1

Abstract: Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines (Ovarian A2780, ADDP Osteosarcoma 143B and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5-7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low microM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study however, many of them showed selective cytotoxicity for the colon tumour cell lines.

Anhydride modified cantharidin analogues. Is ring opening important in the inhibition of protein phosphatase 2A?

Publisher: Elsevier BV

Date: 10-2000

DOI: 10.1016/S0223-5234(00)00186-0

Abstract: A series of anhydride modified cantharidin analogues have been synthesised and screened for their ability to inhibit protein phosphatase 2A. Surprisingly only analogues capable of undergoing a facile ring opening of the anhydride moiety displayed any significant inhibition. Subsequent NMR experiments indicated that 7-oxobicyclo[2.2.1]heptane-2,3-dicarboxylic acid was the major (sole) species under assay conditions. The ability of these modified anhydro-cantharidin analogues to inhibit protein phosphatase 2A varies from 4 (16) to 100% (8) at 100 microM test concentration.

Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors

Publisher: Bentham Science Publishers Ltd.

Date: 30-04-2018

DOI: 10.2174/1389557517666171002161325

Abstract: Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally erse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol. Synthetic efforts toward cyclophillitol, salicinol and derivatives are also highlighted. Importantly, certain metals can inhibit glycosidases and care must be taken to remove residual catalysts from synthetic material to be tested against these enzymes.

Activity and thermal stability of lysozyme in alkylammonium formate ionic liquids—influence of cation modification

Publisher: Royal Society of Chemistry (RSC)

Date: 2009

DOI: 10.1039/B900021F

Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues

Publisher: Wiley

Date: 19-11-2018

DOI: 10.1002/CMDC.201800463

Abstract: Desymmetrisation of robenidine (1: N',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL

Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.TAAP.2013.05.009

Abstract: Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens

Publisher: MDPI AG

Date: 23-09-2022

DOI: 10.3390/ANTIBIOTICS11101301

Abstract: Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.

Amino Alcohol Acrylonitriles as Activators of the Aryl Hydrocarbon Receptor Pathway: An Unexpected MTT Phenotypic Screening Outcome

Publisher: Wiley

Date: 28-02-2020

DOI: 10.1002/CMDC.201900643

Cantharidin analogues: synthesis and evaluation of growth inhibition in a panel of selected tumour cell lines

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0045-2068(02)00524-2

Abstract: Diels-Alder addition of furans (furan, furfuryl alcohol, and 3-bromofuran) to maelic anhydride yields three distinct 5,6-dehydronorcantharidins. Hydrogenation of (4,10-dioxatricyclo[5.2.1.0]decane-3,5-dione) (4a), in dry ethanol affords the monoester (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic aid monoethyl ester) (6). Subsequent transesterification affords a series of monoesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monomethyl ester (7)), 7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monopropyl ester (8), (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid monohexyl ester (9)) and differentially substituted diesters (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-isopropyl ester) (10), and (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-ethyl ester 3-phenyl ester) (11). Analogues were firstly screened for their ability to inhibit protein phosphatases 1 (PP1) and 2A (PP2A) as the lead compounds cantharidin (1) and norcantharidin (2) are known PP1 and PP2A inhibitors. Only analogues 4a, 6-8 displayed good PP1 and PP2A inhibition (PP1 IC(50)'s=2.0, 2.96, 4.71, and 4.82 microM, respectively PP2A IC(50)'s=0.2, 0.45, 0.41, and 0.47 microM, respectively). All analogues were also screened for their anti-cancer potential against a panel of tumour cell lines, HL60, L1210, SW480, WiDr, HT29, HCT116, A2780, ADDP, and 143B, producing GI(50) values ranging from 6 microM to >1000 microM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity.

Metal-Templated Macrocycle Synthesis in an Ionic Liquid: A Comparison With Reaction in Protic Solvents

Publisher: Informa UK Limited

Date: 03-12-2012

DOI: 10.1080/15533174.2011.652275

Effect of template on the formation of phase-inversed molecularly imprinted polymer thin films: an assessment

Publisher: Royal Society of Chemistry (RSC)

Date: 2009

DOI: 10.1039/B902468A

Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 16-08-2007

DOI: 10.1124/MOL.107.034207

Abstract: Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadecyltrimethyl ammonium bromide (OcTMAB), and we now show MiTMAB targets the dynamin-phospholipid interaction. MiTMAB inhibited dynamin GTPase activity, with a Ki of 940 +/- 25 nM. It potently inhibited receptor-mediated endocytosis (RME) of transferrin or epidermal growth factor (EGF) in a range of cells without blocking EGF binding, receptor number, or autophosphorylation. RME inhibition was rapidly reversed after washout. The rank order of potency for a variety of MiTMAB analogs on RME matched the rank order for dynamin inhibition, suggesting dynamin recruitment to the membrane is a primary cellular target. MiTMAB also inhibited synaptic vesicle endocytosis in rat brain nerve terminals (synaptosomes) without inducing depolarization or morphological defects. Therefore, the drug rapidly and reversibly blocks multiple forms of endocytosis with no acute cellular damage. The unique mechanism of action of MiTMAB provides an important tool to better understand dynamin-mediated membrane trafficking events in a variety of cells.

Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells

Publisher: Springer Science and Business Media LLC

Date: 17-01-2013

DOI: 10.1186/1476-4598-12-4

Abstract: During metaphase clathrin stabilises the mitotic spindle kinetochore(K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis. Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition. Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in iding HeLa cells, without affecting iding non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.

Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation.

Publisher: Elsevier BV

Date: 09-2007

DOI: 10.1016/J.BMC.2007.06.034

Abstract: A range of amines was reacted with norcantharidin (2) to provide the corresponding norcantharimides (9-43). Treatment of norcantharidin with allylamine afforded the corresponding allyl-norcantharimide (20) which was amenable to epoxidation (mCPBA, 22) and subsequent ring opening (MeOH/H(+) 23) or alternatively, osmylation (OsO(4)/NMO 24). These simple synthetic modifications of 2 facilitated the development of a novel series of norcantharimides displaying modest to good broad spectrum cytotoxicity against HT29 and SW480 (colorectal carcinoma) MCF-7 (breast adenocarcinoma) A2780 (ovarian carcinoma) H460 (lung carcinoma) A431 (epidermoid carcinoma) DU145 (prostate carcinoma) BE2-C (neuroblastoma) and SJ-G2 (glioblastoma). Analogues possessing a C(10), C(12) or C(14) alkyl chain or a C(12) linked bis-norcantharimide displayed the highest levels of cytotoxicity.

Molecularly imprinted polymers (MIPs): sensing, an explosive new opportunity?

Publisher: Royal Society of Chemistry (RSC)

Date: 2007

DOI: 10.1039/B708660A

Abstract: Our group is currently developing in-field detection systems alongside the Australian Federal Police Forensic Services utilising molecularly imprinted polymers as the recognition elements. This review looks at MIP synthesis and our perceptions of future directions from an Australian and forensic perspective.

Pyrimidyn Compounds: Dual-Action Small Molecule Pyrimidine-Based Dynamin Inhibitors

Publisher: American Chemical Society (ACS)

Date: 30-05-2013

DOI: 10.1021/CB400137P

Molecularly imprinted films of acrylonitrile/methyl methacrylate/acrylic acid terpolymers: influence of methyl methacrylate in the binding performance of l-ephedrine imprinted films

Publisher: Royal Society of Chemistry (RSC)

Date: 2013

DOI: 10.1039/C3OB40332G

Abstract: Molecularly imprinted polymeric films (MIPFs) highly selective to 1R,2S(-)ephedrine (L-ephedrine, EPD) were produced by phase inversion post-polymerization imprinting on poly(acrylonitrile-co-methyl methacrylate-co-acrylic acid) (PAMA) terpolymers. The inclusion of methyl methacrylate (MMA) to the polymer formulation resulted in enhanced EPD selectivity which appears to be dictated by polymer composition to achieve the necessary balance between polymer rigidity and porosity. Substitution of MMA with methyl acrylate, ethyl acrylate and n-butyl acrylate resulted in a loss of EPD selectivity and EPD entrapment within the polymer matrix not observed in PAMA MIPFs. MMA, by virtue of its methyl group, is able to provide the scaffolding and rigidity necessary for stability and preservation of imprinted cavities within the PAMA MIPF leading to high EPD selectivity.

The Role of the HPA Axis in Psychiatric Disorders and CRF Antagonists as Potential Treatments

Publisher: Wiley

Date: 07-2006

DOI: 10.1002/ARDP.200600021

Abstract: An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.

A Flow Chemistry Approach to Norcantharidin Analogues

Publisher: Bentham Science Publishers Ltd.

Date: 07-2011

DOI: 10.2174/157018011795906730

Antigiardial Activity of Novel Guanidine Compounds

Publisher: Wiley

Date: 29-09-2022

DOI: 10.1002/CMDC.202200341

Abstract: From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter‐screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC 50 μM, seven with IC 50 .0 μM. Most active were 2,2′‐ bis {[4‐(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride ( 30 ), 2,2′‐ bis {[4‐(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride ( 32 ), and 2,2′‐bis[(2‐bromo‐4,5‐dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride ( 41 ) with IC 50 =0.2 μM. The maximal observed activity was a 5 h IC 50 value of 0.2 μM for 41 . The clinically used metronidazole was inactive at this timepoint at a concentration of 25 μM. Robenidine off‐target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41 , no Giardia regrowth was noted after 48 h.

Protein‐protein interactions as antibiotic targets: A medicinal chemistry perspective

Publisher: Wiley

Date: 13-07-2018

DOI: 10.1002/MED.21519

Abstract: There are 27 small molecule protein-protein interaction (PPI) modulators in Phase I, II, and III clinical trials targeting cancer, viruses, autoimmune disorders, and as immune suppression agents. Targeting PPIs as an antibiotic drug discovery strategy remains in relative infancy by comparison. However, a number of molecules are in development which target PPI within the replisome, isome, transcriptome, and translatome are showing significant promise at the medicinal chemistry stage of drug development. Hence, the success of future PPI agents as antibiotics will build upon the techniques and design strategies of these molecules.

Calcineurin activity is required for the completion of cytokinesis

Publisher: Springer Science and Business Media LLC

Date: 23-05-2010

DOI: 10.1007/S00018-010-0401-Z

Abstract: Successful completion of cytokinesis requires the spatio-temporal regulation of protein phosphorylation and the coordinated activity of protein kinases and phosphatases. Many mitotic protein kinases are well characterized while mitotic phosphatases are largely unknown. Here, we show that the Ca(2+)- and calmodulin-dependent phosphatase, calcineurin (CaN), is required for cytokinesis in mammalian cells, functioning specifically at the abscission stage. CaN inhibitors induce multinucleation in HeLa cells and prolong the time cells spend connected via an extended intracellular bridge. Upon Ca(2+) influx during cytokinesis, CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II (dynII). At the intracellular bridge, phospho-dynII and CaN are co-localized to dual flanking midbody rings (FMRs) that reside on either side of the central midbody ring. CaN activity and disassembly of the FMRs coincide with abscission. Thus, CaN activity at the midbody plays a key role in regulating the completion of cytokinesis in mammalian cells.

The expanding utility of continuous flow hydrogenation

Publisher: Royal Society of Chemistry (RSC)

Date: 2015

DOI: 10.1039/C5OB01067E

Abstract: There has been an increasing body of evidence that flow hydrogenation enhances reduction outcomes across a wide range of synthetic transformations.

Analysis of synaptic vesicle endocytosis in synaptosomes by high-content screening

Publisher: Springer Science and Business Media LLC

Date: 05-07-2012

DOI: 10.1038/NPROT.2012.070

Abstract: Small molecules modulating synaptic vesicle endocytosis (SVE) may ultimately be useful for diseases where pathological neurotransmission is implicated. Only a small number of specific SVE modulators have been identified to date. Slow progress is due to the laborious nature of traditional approaches to study SVE, in which nerve terminals are identified and studied in cultured neurons, typically yielding data from 10-20 synapses per experiment. We provide a protocol for a quantitative, high-throughput method for studying SVE in thousands of nerve terminals. Rat forebrain synaptosomes are attached to 96-well microplates and depolarized SVE is then quantified by uptake of the dye FM4-64, which is imaged by high-content screening. Synaptosomes that have been frozen and stored can be used in place of fresh synaptosomes, reducing the experimental time and animal numbers required. With a supply of frozen synaptosomes, the assay can be performed within a day, including data analysis.

Role of dynamin in elongated cell migration in a 3D matrix

Publisher: Elsevier BV

Date: 03-2015

DOI: 10.1016/J.BBAMCR.2014.12.008

Abstract: The use of 3-dimensional (3D) collagen gels has yielded new insights into the migratory behaviour of cancer cells. While the large GTPase dynamin has emerged as an important regulator of cancer cell migration and invasion under 2D conditions, its role in 3D migration is unclear. We have used a potent dynamin modulator, a bis-tyrphostin derivative, Ryngo® 1-23, to investigate the role of dynamin in 3D migration in 3 different cell lines. The compound specifically inhibits persistent, elongated 3D migration in U87MG and SMA-560 cells. Treated U87MG cells adopt a rounded morphology that is not due to apoptosis, loss of matrix metalloprotease activity or inhibition of clathrin-mediated endocytosis. Given that Ryngo 1-23 is known to regulate dynamin oligomerisation and actin dynamics at the leading edge, we analysed actin filament distribution. Ryngo 1-23 induced a switch in actin filament organization in 3D cultures resulting in the generation of multiple short actin-rich microspikes. Correlated with the change in actin filament distribution, cells displayed reduced collagen gel contraction. Since acto-myosin force transmission to the extra-cellular matrix underpins persistent, elongated migration, our results suggest that Ryngo 1-23 modulates this process in 3D migration via dynamin-mediated regulation of acto-myosin force transmission to the extra-cellular matrix.

Systematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research

Publisher: Springer Science and Business Media LLC

Date: 03-06-2023

DOI: 10.1038/S41467-023-38952-1

Abstract: Chemical probes have reached a prominent role in biomedical research, but their impact is governed by experimental design. To gain insight into the use of chemical probes, we conducted a systematic review of 662 publications, understood here as primary research articles, employing eight different chemical probes in cell-based research. We summarised (i) concentration(s) at which chemical probes were used in cell-based assays, (ii) inclusion of structurally matched target-inactive control compounds and (iii) orthogonal chemical probes. Here, we show that only 4% of analysed eligible publications used chemical probes within the recommended concentration range and included inactive compounds as well as orthogonal chemical probes. These findings indicate that the best practice with chemical probes is yet to be implemented in biomedical research. To achieve this, we propose ‘the rule of two’: At least two chemical probes (either orthogonal target-engaging probes, and/or a pair of a chemical probe and matched target-inactive compound) to be employed at recommended concentrations in every study.

Ionic liquids as porogens for molecularly imprinted polymers: propranolol, a model study

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C4OB00547C

Abstract: The selectivity and rebinding capacity of molecularly imprinted polymers selective for propranolol ( 1 ) using the room temperature ionic liquids [BMIM][BF 4 ], [BMIM][PF 6 ], [HMIM][PF 6 ] and [OMIM][PF 6 ] and CHCl 3 were examined.

Cytotoxic compounds from Laurencia pacifica

Publisher: Springer Science and Business Media LLC

Date: 20-09-2014

DOI: 10.1186/S13588-014-0008-8

Abstract: The current investigation sought to explore the nature of the secondary metabolites in the algae, Laurencia pacifica . This report details the first isolation of the sesquiterpenes isoaplysin ( 1 ), isolaurenisol ( 2 ), debromoisolaurinterol ( 3 ), debromoaplysinol ( 4 ), laur-11-en-10-ol ( 5 ), 10α-hydroxyldebromoepiaplysin ( 6 ), and the previously unknown 10-bromo-3,7,11,11-tetramethylspiro[5.5]undeca-1,7-dien-3-ol ( 7 ) from the algae, Laurencia pacifica . Isoaplysin ( 1 ) and debromoaplysinol ( 4 ) showed promising levels of growth inhibition against a panel cancer-derived cell lines of colon (HT29), glioblastoma (U87, SJ-G2), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (Du145), neuroblastoma (BE2-C), pancreas (MIA), murine glioblastoma (SMA) origin with average GI 50 values of 23 and 14 μM. Isoaplysin ( 1 ) and debromoaplysinol ( 4 ) were up to fourfold more potent in cancer-derived cell populations than in non-tumor-derived normal cells (MCF10A). These analogues are promising candidates for anticancer drug development.

Actin- and Dynamin-Dependent Maturation of Bulk Endocytosis Restores Neurotransmission following Synaptic Depletion

Publisher: Public Library of Science (PLoS)

Date: 22-05-2012

DOI: 10.1371/JOURNAL.PONE.0036913

Author Correction: Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Publisher: Springer Science and Business Media LLC

Date: 19-02-2021

DOI: 10.1038/S41467-021-21688-1

Abstract: A Correction to this paper has been published: 0.1038/s41467-021-21688-1

A Highly Atom Efficient, Solvent Promoted Addition of Tetraallylic, Tetraallenic, and Tetrapropargylic Stannanes to Carbonyl Compounds

Publisher: American Chemical Society (ACS)

Date: 12-10-2001

DOI: 10.1021/JO015904X

Abstract: Tetraallylic, tetraallenic, and tetrapropargylic stannanes (0.25 equiv) react with aldehydes in methanol to provide unsaturated alcohols in good to excellent yields (56-99%). These reactions proceed exclusively with allylic rearrangement for tetra(2-butenyl)tin 2b and tetra(1,2-butadienyl)tin 16c and predominantly with allylic rearrangement for tetrapropadienyltin 16a and tetra(2-butynyl)tin 6e. Allylation reactions also proceeded smoothly with reactive ketones such as ethyl pyruvate (9a) and cyclohexanone (9b). The corresponding TFA-catalyzed reactions of dimethyl acetals 4d and 4e are regiospecific with allylic rearrangement.

Synthesis of biaryl-styrene monomers by microwave-assisted Suzuki coupling

Publisher: Elsevier BV

Date: 10-2009

DOI: 10.1016/J.TETLET.2009.07.117

Serine/threonine protein phosphatase inhibition enhances the effect of thymidylate synthase inhibition

Publisher: Springer Science and Business Media LLC

Date: 03-2004

DOI: 10.1007/S00280-003-0730-9

Abstract: The serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) are key enzymes in regulating entry into the cell cycle, mitosis and apoptosis. Inhibition of PP1 and PP2A is associated with enhanced S-phase entry culminating in G(2)/M arrest and apoptotic cell death. Thymidylate synthase (TS) is a key regulatory enzyme in DNA synthesis, inhibition of which is often a first-line treatment for colorectal carcinoma. In this study the effect of combining PP inhibition with TS inhibition in two colorectal cell lines was examined. Cantharidin and nolatrexed were used to inhibit PP and TS activity, respectively. The MTT cytotoxicity assay and cell cycle analysis were performed following single-drug treatment of HT29 and HCT116 colorectal cell lines. The median effect method was used to determine a combination index (CI), where drug antagonism was indicated by a CI>1.1, additivity by a CI between 0.9 and 1.1, and synergism by a CI<0.9. Both cell lines were equally sensitive to cantharidin alone (GI(50) values 5.4 and 7.3 micro M), which induced a significant increase in the S-phase population of both cell lines within 6 h with a concomitant increase in DNA synthesis. This response culminated in G(2)/M cell cycle arrest within 24 h and subsequent cell death. In response to nolatrexed alone, HT29 cells were more sensitive than HCT116 cells (GI(50) 1.9 micro M vs 9.8 micro M), with G(1)/S-phase cell cycle arrest occurring within 24 h in both cell lines. In HT29 cells, this was followed by cell death, whereas in HCT116 cells, a proportion of cells died following arrest but the predominant event was re-entry into the cell cycle. The simultaneous exposure of HT29 cells to the combination of nolatrexed and cantharidin in drug molar ratios of 1:1 and 1:2.5 for 72 h was synergistic producing composite CIs of 0.88 and 0.87, respectively. The sequence of nolatrexed followed by cantharidin 24 h later resulted in greater synergism (CI values of 0.75, 0.52, 0.55, 0.68 for molar ratios of 10:1, 1:1, 1:2.5, 1:10), whereas the reverse sequence was antagonistic, suggesting that the point of interaction is downstream of TS inhibition. In HCT116 cells only additive and antagonistic interactions were observed for any of the treatment combinations. The lack of synergism in these cells may be caused by the reduced sensitivity of these cells to nolatrexed as a single agent. The effect of TS inhibition can be enhanced by the inhibition of serine/threonine protein phosphatases.

Modelling and Phenotypic Screening of NAP‐6 and 10‐Cl‐BBQ, AhR Ligands Displaying Selective Breast Cancer Cytotoxicity in Vitro

Publisher: Wiley

Date: 25-02-2021

DOI: 10.1002/CMDC.202000721

Inhibition of Dynamin Mediated Endocytosis by the Dynoles—Synthesis and Functional Activity of a Family of Indoles

Publisher: American Chemical Society (ACS)

Date: 21-05-2009

DOI: 10.1021/JM900036M

Abstract: Screening identified two bisindolylmaleimides as 100 microM inhibitors of the GTPase activity of dynamin I. Focused library approaches allowed development of indole-based dynamin inhibitors called dynoles. 100-Fold in vitro enhancement of potency was noted with the best inhibitor, 2-cyano-3-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N-octylacrylamide (dynole 34-2), a 1.3 +/- 0.3 microM dynamin I inhibitor. Dynole 34-2 potently inhibited receptor mediated endocytosis (RME) internalization of Texas red-transferrin. The rank order of potency for a variety of dynole analogues on RME in U2OS cells matched their rank order for dynamin inhibition, suggesting that the mechanism of inhibition is via dynamin. Dynoles are the most active dynamin I inhibitors reported for in vitro or RME evaluations. Dynole 34-2 is 15-fold more active than dynasore against dynamin I and 6-fold more active against dynamin mediated RME (IC(50) approximately 15 microM RME IC(50) approximately 80 microM). The dynoles represent a new series of tools to better probe endocytosis and dynamin-mediated trafficking events in a variety of cells.

Heterocyclic substituted cantharidin and norcantharidin analogues--synthesis, protein phosphatase (1 and 2A) inhibition, and anti-cancer activity.

Publisher: Elsevier BV

Date: 06-2007

DOI: 10.1016/J.BMCL.2007.03.093

Abstract: Norcantharidin (3) is a potent PP1 (IC(50)=9.0+/-1.4 microM) and PP2A (IC(50)=3.0+/-0.4 microM) inhibitor with 3-fold PP2A selectivity and induces growth inhibition (GI(50) approximately 45 microM) across a range of human cancer cell lines including those of colorectal (HT29, SW480), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (DU145), neuroblastoma (BE2-C), and glioblastoma (SJ-G2) origin. Until now limited modifications to the parent compound have been tolerated. Surprisingly, simple heterocyclic half-acid norcantharidin analogues are more active than the original lead compound, with the morphilino-substituted (9) being a more potent (IC(50)=2.8+/-0.10 microM) and selective (4.6-fold) PP2A inhibitor with greater in vitro cytotoxicity (GI(50) approximately 9.6 microM) relative to norcantharidin. The analogous thiomorpholine-substituted (10) displays increased PP1 inhibition (IC(50)=3.2+/-0 microM) and reduced PP2A inhibition (IC(50)=5.1+/-0.41 microM), to norcantharidin. Synthesis of the analogous cantharidin analogue (19) with incorporation of the amine nitrogen into the heterocycle further increases PP1 (IC(50)=5.9+/-2.2 microM) and PP2A (IC(50)=0.79+/-0.1 microM) inhibition and cell cytotoxicity (GI(50) approximately 3.3 microM). These analogues represent the most potent cantharidin analogues thus reported.

Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition of a New Generation of Cantharidin Analogues

Publisher: Springer Science and Business Media LLC

Date: 02-2002

DOI: 10.1023/A:1014460818734

Abstract: Cantharidin (Spanish Fly) is a natural toxin and an inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A), which have key roles in cell cycle progression. We have synthesised two series of demethylated cantharidin analogues, one displaying an open-ring lactone configuration in solution (Novo-1 to Novo-5) similar to cantharidin, the other showing a closed-ring lactone configuration (Novo-6 to Novo-10). In the present study, these ten agents were screened for in vitro PP1 and PP2A inhibition and cellular cytotoxicity in nine cancer cell lines of haematopoietic (L1210, HL60), ovarian (A2780, ADDP), osteo (143B), and colon (HCT116, HT29, WiDr, SW480) origin and one normal colon cell line (CCD-018). The open-ring series (IC50, PPI=2.0-4.8 microM, PP2A=0.2-0.5 microM) maintained the PP2A selectivity of cantharidin (IC50, PPI=1.8 microM, PP2A=0.2 microM), although some were less potent. The closed-ring series (IC50, PPI=12.5->1000 microM, PP2A=5->1000 microM) were considerably less potent inhibitors, confirming the need of ring opening for inhibition. The cytotoxicity (IC50, 72 h, MTT assay) of cantharidin ranged from 6-15 microM, while the new analogues ranged from 14 to >1000 microM. Cytotoxicity of the agents did not consistently parallel the in vitro potency of protein phosphatase inhibition. A number of analogues showed colon cancer selectivity, particularly Novo-6, where the cytotoxicity ranged from 14-88 microM in the colon cancer cells and 275-680 microM in all other cell lines including normal colon cells. The reason for this selectivity was not apparent and may involve additional intracellular targets. Cell cycle analysis showed cantharidin to enhance cell cycle progression as evident from an increased S-phase population and enhanced DNA synthesis, culminating in G2/M arrest and apoptosis. With Novo-1 and Novo-6, the cell cycle changes paralleled the cytotoxicity responses, with the predominant effect of G2/M cell cycle arrest followed by cell death. In conclusion, we have synthesised new anticancer agents that show selective cytotoxicity in colon cancer cells while remaining inactive in normal colon cells, and which mediate their effects via the G2/M phase of the cell cycle.

A facile, protic ionic liquid route to N-substituted 5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamides and N-substituted 3-oxoisoindoline-4-carboxylic acids

Publisher: Royal Society of Chemistry (RSC)

Date: 2010

DOI: 10.1039/B924835H

Hedgehog signalling pathway inhibitors as cancer suppressing agents

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3MD00334E

From Spanish fly to room-temperature ionic liquids (RTILs): synthesis, thermal stability and inhibition of dynamin 1 GTPase by a novel class of RTILs

Publisher: Royal Society of Chemistry (RSC)

Date: 2008

DOI: 10.1039/B707092F

Anti-malarial, anti-algal, anti-tubercular, anti-bacterial, anti-photosynthetic, and anti-fouling activity of diterpene and diterpene isonitriles from the tropical marine sponge Cymbastela hooperi

Publisher: Royal Society of Chemistry (RSC)

Date: 2011

DOI: 10.1039/C0OB00326C

Abstract: In an investigation into their potential ecological role(s), a group of mainly diterpene isonitriles, nine in total, isolated from the tropical marine sponge Cymbastela hooperi, and the sesquiterpene axisonitrile-3, isolated from the tropical marine sponge Acanthella kletra, were evaluated in a series of bioassays including anti-fouling, anti-algal, anti-photosynthetic, anti-bacterial (Gram +ve and -ve), anti-fungal, and anti-tubercular. The results of these assays showed that all of the tested compounds, with the exception of diterpene 9, were active in at least two of the applied test systems, with axisonitrile-3 (10) and diterpene isonitrile 1 being the two most active compounds overall, closely followed by diterpene isonitrile 3. Based on the results of the photosynthetic study a molecular modelling investigation was undertaken with all of the compounds used in that study. The results showed a positive correlation between reduction in photosynthetic activity and the interaction of the modelled compounds with a potential enzyme active site.

The influence of ionic liquids on the Knoevenagel condensation of 1H-pyrrole-2-carbaldehyde with phenyl acetonitriles – cytotoxic 3-substituted-(1H-pyrrol-2-yl)acrylonitriles

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C3RA47418F

Synthesis and anticancer activity of focused compound libraries from the natural product lead, oroidin

Publisher: Elsevier BV

Date: 03-2014

DOI: 10.1016/J.BMC.2014.01.021

Abstract: Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5 μM were observed with 4l against HT29 (colon) and SW480 (colon) 5a against HT29 and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active.

Diimidazo[1,2-c:4′,5′-e]pyrimidines: N6-N1 conformationally restricted adenosines

Publisher: Elsevier BV

Date: 03-1998

DOI: 10.1016/S0960-894X(98)00101-2

Abstract: Tethering the N6-substituents of N6-substituted adenosines to N1 has resulted in a series of conformationally restricted adenosine analogues. The resultant diimidazo[1,2-c:4',5'-e]pyrimidines were shown to be adenosine A1 selective.

A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6OB01153E

Abstract: A simple flow chemistry approach to libraries of 2-substituted-phenylamino 3,4-dihydro-2 H -benzo[ b ][1,4]oxazine-6-carboxylates ( 12a–l and 13a–l ) in 38–87% yields.

In Silico docking, molecular dynamics and binding energy insights into the bolinaquinone-clathrin terminal domain binding site

Publisher: MDPI AG

Date: 22-05-2014

DOI: 10.3390/MOLECULES19056609

Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity.

Publisher: Elsevier BV

Date: 12-2007

DOI: 10.1016/J.BMC.2007.08.028

Abstract: Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low muM IC(50)s) comparable to that of norcantharidin (PP1 IC(50)=10.3+/-1.37 microM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC(50)=2.69+/-1.37 microM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC(50)=6.5+/-2.3 microM and PP2A IC(50)=7.9+/-0.82 microM (PP1/PP2A=0.82) and a 2,4,6-trimethylaniline, 23, displaying PP1 IC(50)=48+/-9 and PP2A IC(5) 85+/-3 microM (PP1/PP2A=0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC(50)s of 89+/-6 and 42+/-3 microM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.

Green chemistry approaches to the Knoevenagel condensation: comparison of ethanol, water and solvent free (dry grind) approaches

Publisher: Elsevier BV

Date: 04-2002

DOI: 10.1016/S0040-4039(02)00480-X

Characterization of a novel role for the dynamin mechanoenzymes in the regulation of human sperm acrosomal exocytosis

Publisher: Oxford University Press (OUP)

Date: 30-08-2017

DOI: 10.1093/MOLEHR/GAX044

Abstract: Does dynamin regulate human sperm acrosomal exocytosis? Our studies of dynamin localization and function have implicated this family of mechanoenzymes in the regulation of progesterone-induced acrosomal exocytosis in human spermatozoa. Completion of an acrosome reaction is a prerequisite for successful fertilization in all studied mammalian species. It follows that failure to complete this unique exocytotic event represents a common aetiology in the defective spermatozoa of male infertility patients that have failed IVF in a clinical setting. Recent studies have implicated the dynamin family of mechanoenzymes as important regulators of the acrosome reaction in murine spermatozoa. The biological basis of this activity appears to rest with the ability of dynamin to polymerize around newly formed membrane vesicles and subsequently regulate the rate of fusion pore expansion. To date, however, the dynamin family of GTPases have not been studied in the spermatozoa of non-rodent species. Here, we have sought to examine the presence and functional significance of dynamin in human spermatozoa. Dynamin expression was characterized in the testis and spermatozoa of several healthy normozoospermic in iduals. In addition, we assessed the influence of selective dynamin inhibition on the competence of human spermatozoa to undergo a progesterone-induced acrosome reaction. A minimum of five biological and technical replicates were performed to investigate both inter- and intra-donor variability in dynamin expression and establish statistical significance in terms of the impact of dynamin inhibition. The expression and the localization of dynamin in the human testis, epididymis and mature spermatozoa were determined through the application of immunofluorescence, immunoblotting and/or electron microscopy. Human semen s les were fractionated via density gradient centrifugation and the resultant populations of good and poor quality spermatozoa were induced to capacitate and acrosome react in the presence or absence of selective dynamin inhibitors. The acrosome integrity of live spermatozoa was subsequently assessed via the use of fluorescently conjugated Arachis hypogea lectin (PNA). The influence of dynamin phosphorylation and the regulatory kinase(s) responsible for this modification in human spermatozoa were also assessed via the use of in situ proximity ligation assays and pharmacological inhibition. In all experiments, ≥100 spermatozoa were assessed/treatment group and all graphical data are presented as the mean values ± SEM, with statistical significance being determined by ANOVA. Dynamin 1 (DNM1) and DNM2, but not DNM3, were specifically localized to the acrosomal region of the head of human spermatozoa, an ideal position from which to regulate acrosomal exocytosis. In keeping with this notion, pharmacological inhibition of DNM1 and DNM2 was able to significantly suppress the rates of acrosomal exocytosis stimulated by progesterone. Furthermore, our comparison of dynamin expression in good and poor quality spermatozoa recovered from the same ejaculate, revealed a significant reduction in the amount of DNM2 in the latter subpopulation of cells. In contrast, DNM1 was detected at equivalent levels in both subpopulations of spermatozoa. Such findings are of potential significance given that the poor quality spermatozoa proved refractory to the induction of a progesterone stimulated acrosome reaction. In seeking to identify the regulatory influence of progesterone on DNM2 function, we were able to establish that the protein is a substrate for CDK1-dependent phosphorylation. The functional significance of DNM2 phosphorylation was illustrated by the fact that pharmacological inhibition of CDK1 elicited a concomitant suppression of both DNM2-Ser764 phosphorylation and the overall rates of progesterone-induced acrosomal exocytosis. N/A. This was an in vitro study performed mainly on ejaculated human spermatozoa. This experimental paradigm necessarily eliminates the physiological contributions of the female reproductive tract that would normally support capacitation and acrosomal responsiveness. This study identifies a novel causative link between dynamin activity and the ability of human spermatozoa to complete a progesterone-induced acrosome reaction. Such findings encourage a more detailed analysis of the contribution of dynamin dysregulation as an underlying aetiology in infertile males whose spermatozoa are unable to penetrate the zona pellucida. This research was supported by a National Health and Medical Research Council of Australia Project Grant (APP1103176) awarded to B.N. and E.A.M. The authors report no conflict of interest.

Molecular Imprinting of Benzylpiperazine: A Comparison of the Self-Assembly and Semi-Covalent Approaches

Publisher: MDPI AG

Date: 07-03-2023

DOI: 10.3390/IJMS24065117

Abstract: Molecularly imprinted polymers (MIPs) for benzylpiperazine (BZP, 1), an illicit designer drug, were developed by using both self-assembly and semi-covalent approaches. From an array of potential functional monomers (FMs) and using a combination of pre-synthetic interaction studies (by molecular modelling and NMR analysis) and binding assays, the highest performing self-assembly 1-MIPs were confirmed to result from methacrylic acid (7) as FM, ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) as crosslinkers and chloroform as the porogen and rebinding solvent at template (T): FM ratios of 1:1 and 1:2, giving imprinting factors (IF) 3 to 7. The semi-covalent 1-MIPs were designed using benzylpiperazine (4-vinylphenyl) carbamate (16) as the template–monomer adduct in combination with either EDGMA or TRIM. Our comparative analysis showed the semi-covalent polymers to have a stronger affinity for 1 (significantly lower Kd values and higher IFs) and faster uptake than the self-assembly systems. Both approaches have comparable cross-reactivity: marginal to low against cocaine (17) and morphine (18) and high against ephedrine (19) and phenylpiperazine (20). They also have comparable selectivity: highly selective towards 1 against 17, moderate against 18 and non-selective against 19. EGDMA-based self-assembly MIPs displayed a greater imprinting effect (higher IFs and NIP-to-MIP Kd ratios) than TRIM-based MIPs, while the TRIM-based semi-covalent MIP outperformed its EGDMA-based equivalent. By virtue of its modest selectivity against the test illicit drugs, 1-MIPs could potentially be used as a dummy MIP for the broad-based capture and enrichment of illicit drug blends for subsequent laboratory analysis.

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Publisher: Springer Science and Business Media LLC

Date: 04-12-2020

DOI: 10.1038/S41467-020-20091-6

Abstract: Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.

Synthesis and Cytotoxicity of Octahydroepoxyisoindole‐7‐carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues

Publisher: Wiley

Date: 14-05-2019

DOI: 10.1002/CMDC.201900180

Abstract: Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels-Alder reaction of an amine-substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell lines examined: HT29 (colon), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), SJ-G2 and U87 (glioblastoma), MIA (pancreatic), and SMA (spontaneous murine astrocytoma). The incorporation of an amino-substituted system post-synthesis of norcantharidin afforded facile access to 14 acid/amide-substituted norcantharidin analogues. Of these, only four displayed sufficient activity at the initial 25 μm compound screening dose to warrant full evaluation of growth inhibition. Common to these analogues was the presence of a 4-biphenyl moiety, and in particular 3-(2-(furan-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (13 c) and 3-(2-(pyrrole-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24) displayed high levels of cytotoxicity, returning GI

Pharmacophore Development for Corticotropin-Releasing Hormone:  New Insights into Inhibitor Activity

Publisher: American Chemical Society (ACS)

Date: 08-06-1999

DOI: 10.1021/JM9900117

Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain

Publisher: American Chemical Society (ACS)

Date: 20-12-2016

DOI: 10.1021/ACS.JMEDCHEM.6B01422

Abstract: The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC

Synthesis and Evaluation of a Molecularly Imprinted Polymer Selective to 2,4,6-Trichloroanisole

Publisher: CSIRO Publishing

Date: 2006

DOI: 10.1071/CH05318

Abstract: In the wine industry 2,4,6-trichloroanisole (TCA) has been identified as the primary contaminant responsible for ‘cork taint’. A molecularly imprinted polymer (MIP) selective for TCA was prepared in three porogens (hexane, acetonitrile, and dichloromethane) of varying polarities using non-covalent molecular imprinting techniques. Target rebinding to the MIP was found to be most effective in its porogenic solvent and highest in dichloromethane (imprinting factor = 3.65). Competitive binding assays performed against a range of close structural analogues demonstrated a preference for the target molecule.

Long chain amines and long chain ammonium salts as novel inhibitors of dynamin GTPase activity

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1016/J.BMCL.2004.03.096

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

Publisher: Wiley

Date: 12-11-2019

DOI: 10.1002/MED.21645

Abstract: Breast cancer is the most common cancer in women, with more than 1.7 million diagnoses worldwide per annum. Metastatic breast cancer remains incurable, and the presence of triple-negative phenotypes makes targeted treatment impossible. The aryl hydrocarbon receptor (AhR), most commonly associated with the metabolism of xenobiotic ligands, has emerged as a promising biological target for the treatment of this deadly disease. Ligands for the AhR can be classed as exogenous or endogenous and may have agonistic or antagonistic activity. It has been well reported that agonistic ligands may have potent and selective growth inhibition activity in a number of oncogenic cell lines, and one (aminoflavone) has progressed to phase I clinical trials for breast cancer sufferers. In this study, we examine the current state of the literature in this area and elucidate the promising advances that are being made in hijacking the cytosolic-to-nuclear pathway of the AhR for the possible future treatment of breast cancer.

Synthesis and biological activity of Δ-5,6-norcantharimides: importance of the 5,6-bridge

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.EJMECH.2010.01.004

Abstract: Cantharidin (1) and norcantharidin (2) are potent protein phosphatase 1 and 2A inhibitors that also display high levels of anticancer activity against a broad range of tumor cells lines. Surprisingly, Delta-5,6-ethyl norcantharidin (3, cis-tetrahydrofurano[3,4-c]furan-1,3-dione) displays neither phosphatase inhibition nor anticancer activity. This suggests that the 5,6-ethyl bridge is pivotal to both anti-cancer and protein phosphatase activity. Additionally bioisosteric replacement of the ethereal oxygen has no effect on biological activity nor does modification of the anhydride moiety. Unlike the parent norcantharidin, anhydride ring opening has no effect on either protein phosphatase inhibition or anti-cancer activity. Additionally, this work highlights the discovery of the octyl substituted, cis-5-benzyl-2-hexyltetrahydro-2H,3aH-pyrrolo[3,4-c]pyrrole-1,3-dione, 9p, and the octyl substituted, cis-octyltetrahydro-5H-furo[3,4-c]pyrrole-4,6-dione, 8p, as two new cytotoxic agents which are equipotent (9p) with, and more potent (8p) than norcantharidin.

Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells

Publisher: Rockefeller University Press

Date: 16-08-2010

DOI: 10.1083/JCB.201002119

Abstract: Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects of these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times the volume internalized by the clathrin-mediated endocytic pathway, forming the major pathway involved in uptake of fluid and bulk membrane in fibroblasts. Electron tomographic analysis of the 3D morphology of the earliest carriers shows that they are multidomain organelles that form a complex sorting station as they mature. Proteomic analysis provides direct links between CLICs, cellular adhesion turnover, and migration. Consistent with this, CLIC-mediated endocytosis of key cargo proteins, CD44 and Thy-1, is polarized at the leading edge of migrating fibroblasts, while transient ablation of CLICs impairs their ability to migrate. These studies provide the first quantitative ultrastructural analysis and molecular characterization of the major endocytic pathway in fibroblasts, a pathway that provides rapid membrane turnover at the leading edge of migrating cells.

Microwave induced MIP synthesis: comparative analysis of thermal and microwave induced polymerisation of caffeine imprinted polymers

Publisher: Royal Society of Chemistry (RSC)

Date: 2010

DOI: 10.1039/B9NJ00538B

Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors

Publisher: Elsevier BV

Date: 02-2013

DOI: 10.1016/J.TCB.2012.10.007

Abstract: Many pathogens hijack existing endocytic trafficking pathways to exert toxic effects in cells. Dynamin controls various steps of the intoxication process used by numerous pathogenic bacteria, viruses, and toxins. Targeting dynamin with pharmaceutical compounds may therefore have prophylactic potential. Here we review the growing number of pathogens requiring dynamin-dependent trafficking to intoxicate cells, outline the mode of internalization that leads to their pathogenicity, and highlight the protective effect of pharmacological and genetic approaches targeting dynamin function. We also assess the methodologies used to investigate the role of dynamin in the intoxication process and discuss the validity and potential pitfalls of using dynamin inhibitors (DIs) as therapeutics.

Cytotoxic 2-phenyacrylnitriles, the importance of the cyanide moiety and discovery of potent broad spectrum cytotoxic agents

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1016/J.EJMECH.2012.09.019

Abstract: We previously reported the discovery of a simple conjugated cyano pharmacophore which had led to the development of (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile, as a selective inhibitor of oestrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Further exploration though modification of the acrylonitrile and aromatic substituents has highlighted key structural components necessary for broad spectrum cytotoxicity. The acrylic acid derivates (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylic acid and (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid (9) were inactive confirming the importance of the cyanide moiety. The most potent 2-phenylacrylonitriles synthesized were (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-3-yl)acrylonitrile and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI(50) values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI(50) values of ≤8.4 μM. In the case of indole, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead.

Discovery of 4,6-bis(2-((E)-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity

Publisher: Wiley

Date: 07-2019

DOI: 10.1002/OPEN.201800241

Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis

Publisher: American Chemical Society (ACS)

Date: 27-05-2010

DOI: 10.1021/JM100119C

Abstract: Herein we report the synthesis of discrete iminochromene ("iminodyn") libraries (14-38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC(50) values of 260 nM to 100 microM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC(50) values of 330 +/- 70, 450 +/- 50, and 260 +/- 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC(50) values of 10.7 +/- 4.5 and 99.5 +/- 1.7 microM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.

Prodrugs of the Archetypal Dynamin Inhibitor Bis‐T‐22

Publisher: Wiley

Date: 09-11-2022

DOI: 10.1002/CMDC.202200400

Abstract: The Bis‐T series of compounds comprise some of the most potent inhibitors of dynamin GTPase activity yet reported, e. g., (2 E ,2′ E )‐ N , N ′‐(propane‐1,3‐diyl)bis(2‐cyano‐3‐(3,4‐dihydroxyphenyl)acrylamide) ( 2 ), Bis‐T‐22. The catechol moieties are believed to limit cell permeability, rendering these compounds largely inactive in cells. To solve this problem, a prodrug strategy was envisaged and eight ester analogues were synthesised. The shortest and bulkiest esters (acetate and butyl/ tert ‐butyl) were found to be insoluble under physiological conditions, whilst the remaining five were soluble and stable under these conditions. These five were analysed for plasma stability and half‐lives ranged from ∼2.3 min (propionic ester 4 ), increasing with size and bulk, to greater than 24 hr (dimethyl carbamate 10 ). Similar profiles where observed with the rate of formation of Bis‐T‐22 with half‐lives ranging from ∼25 mins (propionic ester 4 ). Propionic ester 4 was chosen to undergo further testing and was found to inhibit endocytosis in a dose‐dependent manner with IC 50 ∼8 μM, suggesting this compound is able to effectively cross the cell membrane where it is rapidly hydrolysed to the desired Bis‐T‐22 parent compound.

Synthesis of Dynole 34-2, Dynole 2-24 and Dyngo 4a for investigating dynamin GTPase

Publisher: Springer Science and Business Media LLC

Date: 20-03-2014

DOI: 10.1038/NPROT.2014.046

Abstract: Dynamin is a large GTPase with roles in membrane fission during clathrin-mediated endocytosis, in actin dynamics and in cytokinesis. Defects in dynamin have been linked to human diseases. The synthesis of a dynamin modulator toolkit comprising two different inhibitor classes is described. The first series comprises Dynole 34-2, Dynole 2-24 and the inactive control Dynole 31-2. The Dynole compounds act on the dynamin G domain, are not GTP competitive and can be synthesized in 2-3 d. Knoevenagel condensation of 1-(3-(dimethylamino)propyl)-1H-indole-3-carbaldehyde (1) with cyanoamides (2 and 3) affords Dynole 31-2 and Dynole 34-2, respectively. Reductive amination of 1 with decylamine gives Dynole 2-24. The second series acts at an allosteric site in the G domain of dynamin and comprises Dyngo 4a and Dyngo Ø (inactive control). Both are synthesized in an overnight reaction via condensation of 3-hydroxy-2-naphthoic hydrazide with 2,4,5-trihydroxybenzaldehyde to afford Dyngo 4a, or with benzaldehyde to afford Dyngo Ø.

Amino Alcohols as Potential Antibiotic and Antifungal Leads

Publisher: MDPI AG

Date: 22-03-2022

DOI: 10.3390/MOLECULES27072050

Abstract: Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed % inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing % inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.

Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors

Publisher: Royal Society of Chemistry (RSC)

Date: 2016

DOI: 10.1039/C6OB00606J

Abstract: A series of quinolone-2-(1 H )-ones derived from a Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line.

Novel Piperazine-1,2,3-Triazole Leads for the Potential Treatment of Pancreatic Cancer

Publisher: Royal Society of Chemistry (RSC)

Date: 2023

DOI: 10.1039/D2MD00289B

Abstract: From lead 1 , (N-(4-((4-(3-(4-(3-methoxyphenyl)-1 H -1,2,3-triazol-1-yl)propyl)piperazin-1-yl)sulfonyl)-phenyl)acetamide), a S100A2-p53 protein-protein interaction inhibitor based on an in silico modelling driven hypothesis, four focused libraries were designed and synthesised. Growth inhibition screening was performed against...

BiCl3-mediated opening of epoxides, a facile route to chlorohydrins or amino alcohols: one reagent, two paths

Publisher: Elsevier BV

Date: 11-2005

DOI: 10.1016/J.TETLET.2005.09.088

Evaluation of 4-substituted styrenes as functional monomers for the synthesis of theophylline-specific molecularly imprinted polymers

Publisher: Royal Society of Chemistry (RSC)

Date: 2014

DOI: 10.1039/C4OB00517A

Abstract: Six novel functional monomers ( M1–M6 ) were examined for their ability to imprint theophylline ( 1 ). The best selectivity was observed with M2 .

Aminoguanidines: New leads for treatment of Giardia duodenalis infection

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1016/J.IJPDDR.2019.04.003

Investigation of the one-pot synthesis of quinolin-2-(1H)-ones and the discovery of a variation of the three-component Ugi reaction

Publisher: Royal Society of Chemistry (RSC)

Date: 2011

DOI: 10.1039/C0OB00029A

Abstract: Rapid access to the quinolin-2-(1H)-one scaffold is afforded by a sequential 4 component Ugi–Knoevenagel condensation of an aminophenylketone, an aromatic aldehyde possessing electron donating moieties, cyanoacetic acid and an aliphatic isocyanide, in moderate to good yields (49–71%). Interestingly, when the reaction is performed using aromatic aldehydes bearing electron withdrawing moieties or isocyanides containing aromatic or ester units, a mixture of a quinolin-2-(1H)-one and an α-amino amide (Ugi three-component adduct) is afforded in varying ratios. Further when the reaction is performed utilizing a combination of an isocyanide-containing aromatic or carbonyl unit, and an aldehyde possessing an electron withdrawing functionality, the Ugi three-component adduct is exclusively afforded. In our hands this new variation of the Ugi 3CR proved to be efficient and robust affording analogues in good yields (51–70%).

The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro

Publisher: MDPI AG

Date: 31-01-2019

DOI: 10.3390/MOLECULES24030524

Abstract: Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM–100 µM) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.

Dichlorophenylacrylonitriles as AhR Ligands That Display Selective Breast Cancer Cytotoxicity in vitro

Publisher: Wiley

Date: 02-07-2018

DOI: 10.1002/CMDC.201800256

Abstract: Knoevenagel condensation of 3,4-dichloro- and 2,6-dichlorophenylacetonitriles gave a library of dichlorophenylacrylonitriles. Our leads (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (5) and (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile (6) displayed 0.56±0.03 and 0.127±0.04 μm growth inhibition (GI

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model

Publisher: MDPI AG

Date: 06-01-2022

DOI: 10.3390/ANTIBIOTICS11010065

Abstract: In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical ersity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1–2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2–4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.

A simple one pot procedure for the generation of homoallylic alcohols from acetals and amino acetals

Publisher: Elsevier BV

Date: 07-1997

DOI: 10.1016/S0040-4039(97)01106-4

Discovery Projects - Grant ID: DP140101565

Start Date: 05-2014

End Date: 06-2018

Amount: $430,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0453490

Start Date: 04-2004

End Date: 07-2007

Amount: $190,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE130100222

Start Date: 02-2013

End Date: 12-2014

Amount: $180,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0342988

Start Date: 2003

End Date: 12-2007

Amount: $50,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100170

Start Date: 01-2012

End Date: 12-2013

Amount: $580,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0210107

Start Date: 2002

End Date: 12-2006

Amount: $205,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0454170

Start Date: 2004

End Date: 06-2005

Amount: $187,341.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP110100984

Start Date: 07-2011

End Date: 12-2016

Amount: $735,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP110200770

Start Date: 11-2011

End Date: 12-2016

Amount: $428,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180101781

Start Date: 02-2018

End Date: 12-2022

Amount: $802,912.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0882285

Start Date: 05-2008

End Date: 12-2010

Amount: $670,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP1095780

Start Date: 06-2010

End Date: 06-2013

Amount: $438,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0883095

Start Date: 2008

End Date: 08-2009

Amount: $750,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0346876

Start Date: 2002

End Date: 12-2003

Amount: $1,584,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0454992

Start Date: 07-2004

End Date: 09-2008

Amount: $171,336.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100142

Start Date: 2010

End Date: 07-2011

Amount: $500,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0561173

Start Date: 2005

End Date: 12-2005

Amount: $207,189.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989105

Start Date: 2009

End Date: 11-2009

Amount: $495,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP210301109

Start Date: 12-2023

End Date: 12-2026

Amount: $282,339.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE180100050

Start Date: 2018

End Date: 04-2019

Amount: $744,100.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE110100078

Start Date: 02-2011

End Date: 12-2011

Amount: $500,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100150

Start Date: 2010

End Date: 12-2012

Amount: $500,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0775378

Start Date: 05-2008

End Date: 12-2009

Amount: $378,942.00

Funder: Australian Research Council