Publications by authors named "Rachel L Clark"

10 Publications

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Identification and development of the 1,4-benzodiazepin-2-one and quinazoline-2,4-dione scaffolds as submicromolar inhibitors of HAT.

Bioorg Med Chem 2012 Oct 31;20(20):6019-33. Epub 2012 Aug 31.

Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.

A library of 1,4-benzodiazepines has been synthesised and evaluated for activity against Trypanosoma brucei, a causative parasite of Human African Trypanosomiasis (HAT). The most potent of these derivatives has an MIC value of 0.97 μM. Herein we report the design, synthesis and biological evaluation of the abovementioned compounds.
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http://dx.doi.org/10.1016/j.bmc.2012.08.049DOI Listing
October 2012

Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines.

Bioorg Med Chem 2011 Jul 24;19(13):3983-94. Epub 2011 May 24.

School of Pharmacy and Applied Science, La Trobe University, Bendigo, Australia.

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.
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http://dx.doi.org/10.1016/j.bmc.2011.05.032DOI Listing
July 2011

Synthesis and biological evaluation of 1,4-benzodiazepin-2-ones with antitrypanosomal activity.

Bioorg Med Chem 2011 Mar 14;19(5):1802-15. Epub 2011 Jan 14.

School of Science, University of Greenwich at Medway, Chatham, UK.

A library of 1,4-benzodiazepines has been synthesized and evaluated against Trypanosoma brucei, a causative parasite of Human African trypanosomiasis. Benzodiazepines possessing a P2- transporter motif were found to have MIC values as low as 0.78 μM.
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http://dx.doi.org/10.1016/j.bmc.2011.01.010DOI Listing
March 2011

The Drug Discovery Portal: a resource to enhance drug discovery from academia.

Drug Discov Today 2010 Aug 12;15(15-16):679-83. Epub 2010 Jun 12.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK.

Drug discovery in universities is usually associated with research on drug targets and mechanisms, but more recently there have been efforts to progress from target studies to proof of concept by applying commercially focussed medicinal chemistry. This creates more opportunities for novel interactions and partnering models between academic groups and pharmaceutical companies. We present a review of coordinated, multi-institutional drug discovery operations within academia that are engaging with industry nationally and internationally and describe how the Drug Discovery Portal at the University of Strathclyde enhances the possibilities for academic drug discovery.
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http://dx.doi.org/10.1016/j.drudis.2010.06.003DOI Listing
August 2010

Current strategies for drug discovery through natural products.

Expert Opin Drug Discov 2010 Jun 6;5(6):559-68. Epub 2010 May 6.

University of Strathclyde, Strathclyde Institute of Pharmacy and Biomedical Sciences, 27 Taylor Street, Glasgow G4 0NR, UK +44 141 553 4155 ; +44 141 552 8376 ;

Importance To The Field: Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Areas to be covered: Current drug discovery strategies involving natural products are described in three sections: developments from traditionally used medicines, random testing of natural compounds on biological assays and use of virtual screening techniques with structures of natural products.

What The Reader Will Gain: The reader will gain an insight into the potential for natural products in current drug discovery paradigms, particularly in the value of using natural products in virtual screening approaches.

Take Home Message: Drug discovery would be enriched if fuller use was made of the chemistry of natural products.
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http://dx.doi.org/10.1517/17460441.2010.488263DOI Listing
June 2010

The drug discovery portal: a computational platform for identifying drug leads from academia.

Curr Pharm Des 2010 May;16(15):1697-702

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued. This invaluable resource has been harnessed to form the basis of the DDP library, and has attracted a high-percentage uptake from the Universities and Research Groups internationally. Its unique attributes include the diversity of the academic database, sourced from synthetic, medicinal and phytochemists working an academic laboratories and the ability to link biologists with appropriate chemical expertise through a target-matching virtual screening approach, and has resulted in seven emerging hit development programmes between international contributors.
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http://dx.doi.org/10.2174/138161210791164018DOI Listing
May 2010

Metabolism of two new benzodiazepine-type anti-leishmanial agents in rat hepatocytes and hepatic microsomes and their interaction with glutathione in macrophages.

J Pharm Pharmacol 2009 Mar;61(3):399-406

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.

Objectives: To measure the metabolism and toxicity of 7-chloro-4-(cyclohexylmethyl)-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (BNZ-1) and 4-cyclohexylmethyl-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (BNZ-2), two new benzodiazepine analogues found to be effective against Leishmania amastigotes in vitro.

Methods: The metabolism of BNZ-1 and -2 was investigated in isolated rat hepatocytes and rat liver microsomes. The toxicity of the compounds was assessed in a murine macrophage cell line by determining cell viability and reduced glutathione (GSH) content. The metabolism and toxicity of flurazepam was assessed for comparison.

Key Findings: BNZ-1 and BNZ-2 underwent similar metabolic transformations by the liver systems, forming N-demethylated and hydroxylated metabolites, with subsequent O-glucuronidation. Flurazepam and both analogue compounds depleted macrophage GSH levels without affecting cell viability at the concentrations used (up to 100 microM), but only flurazepam inhibited glutathione reductase activity, indicating that it is acting by a different mechanism.

Conclusions: The exact mechanism responsible for GSH depletion is unknown at present. Further experiments are needed to fully understand the effects of BNZs on the parasite GSH analogue, trypanothione, which may be a direct or indirect target for these agents. Pharmacokinetic evaluation of these compounds is required to further progress their development as potential new treatments for leishmaniasis.
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http://dx.doi.org/10.1211/jpp/61.03.0017DOI Listing
March 2009

Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics.

Bioorg Med Chem 2007 Jul 6;15(14):4741-52. Epub 2007 May 6.

Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.

The benzo[c]phenanthridines (BCPs) are a group of compounds that are believed to express their antitumor activity through the inhibition of topoisomerase I. The enzyme is crucial to cell cycle division and progression, and regulates the equilibrium between relaxed and supercoiled DNA that occurs during DNA replication. Over the years, we have prepared a number of BCPs and employed a number of biophysical techniques to explore their mechanism of action and improve their activity against this particular enzyme. The naturally occurring alkaloid fagaronine 1 and the synthetic compound ethoxidine 3 are two of the most active compounds, although their inhibitory mechanisms are different, being a poison and suppressor, respectively. We have modified the approach of steered molecular dynamics to create a torque on the intercalator to comprehensively sample the DNA binding site, and using topoisomerase I crystal structures, have proposed a model to explain the different mechanisms of action for these two BCP compounds.
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http://dx.doi.org/10.1016/j.bmc.2007.05.002DOI Listing
July 2007

Identification of the benzodiazepines as a new class of antileishmanial agent.

Bioorg Med Chem Lett 2007 Feb 6;17(3):624-7. Epub 2006 Nov 6.

Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.

The continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with HIV co-infection mean the search for new antileishmanial agents has never been more urgent. We have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macrophages.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.004DOI Listing
February 2007

A modelling study of a non-concerted hydrolytic cycloaddition reaction by the catalytic antibody H11.

Bioorg Med Chem 2006 Apr 27;14(8):2674-83. Epub 2005 Dec 27.

Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow G4 0NR, UK.

H11 is the first antibody reported to have dual activity as a non-concerted, Diels-Alderase and hydrolytic catalyst. It was previously shown to catalyse the cycloaddition of acetoxybutadiene 1a to N-alkyl maleimides 2 to afford hydroxy-substituted bicyclic adducts 3 with a 30% ee of a major isomer. To better understand this mechanism and the partial stereospecificity, a homology model of H11 was constructed and used in docking studies to evaluate potential antibody-ligand complexes. The model suggested the hydrolytic nature of H11 was due to Glu 95H acting as a catalytic base, and evaluation of the shape complementarity of the proposed antibody-ligand complexes confirmed at a semi-quantitative level the observation that the major enantiomer is produced in a 30% ee.
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http://dx.doi.org/10.1016/j.bmc.2005.11.042DOI Listing
April 2006
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