Publications by authors named "Murray N Robertson"

11 Publications

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Inhibitory Kappa B Kinase α (IKKα) Inhibitors That Recapitulate Their Selectivity in Cells against Isoform-Related Biomarkers.

J Med Chem 2017 08 15;60(16):7043-7066. Epub 2017 Aug 15.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0NR, Scotland, United Kingdom.

IKKβ plays a central role in the canonical NF-kB pathway, which has been extensively characterized. The role of IKKα in the noncanonical NF-kB pathway, and indeed in the canonical pathway as a complex with IKKβ, is less well understood. One major reason for this is the absence of chemical tools designed as selective inhibitors for IKKα over IKKβ. Herein, we report for the first time a series of novel, potent, and selective inhibitors of IKKα. We demonstrate effective target engagement and selectivity with IKKα in U2OS cells through inhibition of IKKα-driven p100 phosphorylation in the noncanonical NF-kB pathway without affecting IKKβ-dependent IKappa-Bα loss in the canonical pathway. These compounds represent the first chemical tools that can be used to further characterize the role of IKKα in cellular signaling, to dissect this from IKKβ and to validate it in its own right as a target in inflammatory diseases.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578373PMC
August 2017

Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.

ACS Cent Sci 2016 Oct 14;2(10):687-701. Epub 2016 Sep 14.

Donnelly Centre for Cellular and Biomolecular Research, University of Toronto , 160 College Street, Toronto, Ontario M5S 3E1, Canada.

The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work.
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http://dx.doi.org/10.1021/acscentsci.6b00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084075PMC
October 2016

Experiences with a researcher-centric ELN.

Chem Sci 2015 Mar 20;6(3):1614-1629. Epub 2014 Oct 20.

Chemistry , University of Southampton , Southampton , SO17 1BJ , UK . Email:

Electronic Laboratory Notebooks (ELNs) are progressively replacing traditional paper books in both commercial research establishments and academic institutions. University researchers require specific features from ELNs, given the need to promote cross-institutional collaborative working, to enable the sharing of procedures and results, and to facilitate publication. The LabTrove ELN, which we use as our exemplar, was designed to be researcher-centric (, not only aimed at the individual researcher's basic needs rather than to a specific institutional or subject or disciplinary agenda, but also able to be tailored because it is open source). LabTrove is being used in a heterogeneous set of academic laboratories, for a range of purposes, including analytical chemistry, X-ray studies, drug discovery and a biomaterials project. Researchers use the ELN for recording experiments, preserving data collected, and for project coordination. This perspective article describes the experiences of those researchers from several viewpoints, demonstrating how a web-based open source electronic notebook can meet the diverse needs of academic researchers.
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http://dx.doi.org/10.1039/c4sc02128bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639792PMC
March 2015

Activity of praziquantel enantiomers and main metabolites against Schistosoma mansoni.

Antimicrob Agents Chemother 2014 Sep 30;58(9):5466-72. Epub 2014 Jun 30.

Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland

A racemic mixture of R and S enantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though the S enantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth side-by-side studies are lacking. The aim of this study was to investigate the in vitro activities of PZQ and its main metabolites, namely, R- and S-cis- and R- and S-trans-4'-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored the in vivo activity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations of R-PZQ, S-PZQ, and R-trans- and R-cis-4'-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 μg/ml, respectively, for adult S. mansoni were determined in vitro. S-trans- and S-cis-4'-hydroxypraziquantel were not active at 100 μg/ml. These results are consistent with microcalorimetry data and studies with NTS. In vivo, single 400-mg/kg oral doses of R-PZQ and S-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treated in vivo with S-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm that R-PZQ is the main effector molecule, while S-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ.
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http://dx.doi.org/10.1128/AAC.02741-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135865PMC
September 2014

In vitro metabolic profile and in vivo antischistosomal activity studies of (η(6)-praziquantel)Cr(CO)3 derivatives.

J Med Chem 2013 Nov 12;56(22):9192-8. Epub 2013 Nov 12.

Institute of Inorganic Chemistry and §Institute of Molecular Cancer Research, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05).
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http://dx.doi.org/10.1021/jm401287mDOI Listing
November 2013

Open source drug discovery - a limited tutorial.

Parasitology 2014 Jan 28;141(1):148-57. Epub 2013 Aug 28.

School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.

Open science is a new concept for the practice of experimental laboratory-based research, such as drug discovery. The authors have recently gained experience in how to run such projects and here describe some straightforward steps others may wish to take towards more openness in their own research programmes. Existing and inexpensive online tools can solve many challenges, while some psychological barriers to the free sharing of all data and ideas are more substantial.
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http://dx.doi.org/10.1017/S0031182013001121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884843PMC
January 2014

Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines.

Eur J Med Chem 2012 Nov 5;57:85-101. Epub 2012 Sep 5.

School of Pharmacy and Applied Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia.

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a-g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs(2)CO(3) to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a-i, 13a-c, and 15a-f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19-31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC(50) of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a-b, 15a-b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC(50) for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K. Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19-31 within the binding pocket and structure-activity relationships (SAR) analyses were performed with results agreeing well with observed activities.
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http://dx.doi.org/10.1016/j.ejmech.2012.08.035DOI Listing
November 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

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

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

Characterization of Aquifex aeolicus 4-diphosphocytidyl-2C-methyl-d-erythritol kinase - ligand recognition in a template for antimicrobial drug discovery.

FEBS J 2008 Jun 16;275(11):2779-94. Epub 2008 Apr 16.

Division of Biological Chemistry and Drug Discovery, University of Dundee, UK.

4-Diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE) catalyses the ATP-dependent conversion of 4-diphosphocytidyl-2C-methyl-D-erythritol (CDPME) to 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate with the release of ADP. This reaction occurs in the non-mevalonate pathway of isoprenoid precursor biosynthesis and because it is essential in important microbial pathogens and absent from mammals it represents a potential target for anti-infective drugs. We set out to characterize the biochemical properties, determinants of molecular recognition and reactivity of IspE and report the cloning and purification of recombinant Aquifex aeolicus IspE (AaIspE), kinetic data, metal ion, temperature and pH dependence, crystallization and structure determination of the enzyme in complex with CDP, CDPME and ADP. In addition, 4-fluoro-3,5-dihydroxy-4-methylpent-1-enylphosphonic acid (compound 1) was designed to mimic a fragment of the substrate, a synthetic route to 1 was elucidated and the complex structure determined. Surprisingly, this ligand occupies the binding site for the ATP alpha-phosphate not the binding site for the methyl-D-erythritol moiety of CDPME. Gel filtration and analytical ultracentrifugation indicate that AaIspE is a monomer in solution. The enzyme displays the characteristic alpha/beta galacto-homoserine-mevalonate-phosphomevalonate kinase fold, with the catalytic centre positioned in a deep cleft between the ATP- and CDPME-binding domains. Comparisons indicate a high degree of sequence conservation on the IspE active site across bacterial species, similarities in structure, specificity of substrate recognition and mechanism. The biochemical characterization, attainment of well-ordered and reproducible crystals and the models resulting from the analyses provide reagents and templates to support the structure-based design of broad-spectrum antimicrobial agents.
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http://dx.doi.org/10.1111/j.1742-4658.2008.06418.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2655357PMC
June 2008