Department of Pharmacy and Pharmacology

andrew_thompson

Senior Lecturer in Medicinal Chemistry

5 West - 2.15

Email: A.S.Thompson@bath.ac.uk

Tel: +44 (0) 1225 386765 

 

Dr Andrew Thompson 

Profile

Research Interests

Studies on the DNA Duplex Adducts of Anti-cancer agents by High Field NMR

The central target of my research is aimed at determining the molecular basis for the anti-tumour activity of DNA interactive anti-cancer ligands. It is hoped that we will be able relate the structural changes in local DNA structure which are induced or entrapped by these ligands to the biochemical and biological effects and incorporate these findings into the design of future DNA interactive anti-cancer ligands.

A number of methods are available to study the structure and nature of ligand-DNA adducts, these include X-ray diffraction, high-field NMR, circular dichroism, Raman spectroscopy, UV, IR, gel electrophoresis and enzymatic probes. My research has concentrated on the use of high-field NMR coupled with molecular modelling to closely study the duplex adducts formed in the reactions of DNA alkylating ligands and DNA duplexes.

High field NMR studies are performed on the in-house Varian 600MHz and 400Mhz NMR spectrometers and a typical range of two-dimensional experiments are employed including NOESY, ROESY, TOCSY, PE-COSY, DQF-COSY, 1H-31P HMBC and 1H-15N HMBC (where 15N labelled adducts were available). Data from these experiments is used to confirm molecular connectivity and provide insight into bond angles and DNA sugar conformations. They also provide via NOESY spectroscopy accurate through-space distances between protons on neighbouring substituents.

This NOESY (distance) and COSY (angle) data is then interpreted by programs such as MARDIGRAS, SPHINX-LINSHA and PSEUROT in order to generate accurate 1H-1H distances and bond torsional angle restraints which are used to drive extensive molecular modelling studies. Molecular modelling studies involve both unrestrained and restrained mechanics and dynamics calculations using Sybyl / AMBER on Silicon Graphics R12000 workstations. Results of these calculations were then examined both visually by MIDAS Plus and MD Display or with the aid of software tools like DIALS AND WINDOWS to confirm and visualise the structural data obtained.

Current targets that we are interested in investigrating include the unique DNA quadraplex found in the telomers of DNA, and the study of larger adducts incorporating partially (or fully) deuteraterated protein fragments by on to allow complete assignment of the adduct and the use of DOSY NMR spectroscopy to study the interactions of weaker DNA interactive ligands that do not form stable duplex adducts

Publications

Nathubhai, A., Haikarainen, T., Hayward, P. C., Munoz-Descalzo, S., Thompson, A. S., Lloyd, M. D., Lehtio, L. and Threadgill, M., 2016. Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases. European Journal of Medicinal Chemistry, 118, pp. 316-327.

Paine, H. A., Nathubhai, A., Woon, E. C. Y., Sunderland, P. T., Wood, P. J., Mahon, M. F., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Narwal, M., Lehtio, L. and Threadgill, M. D., 2015. Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. Bioorganic and Medicinal Chemistry, 23 (17), pp. 5891-5908.

Twum, E. A., Nathubhai, A., Wood, P. J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2015. Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems. Bioorganic and Medicinal Chemistry, 23 (13), pp. 3481-3489.

Kumpan, K., Nathubhai, A., Zhang, C., Wood, P. J., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Lehtio, L. and Threadgill, M. D., 2015. Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Bioorganic and Medicinal Chemistry, 23, pp. 3013-3032.

Threadgill, Michael, 2014. Use of new and known pyridine or pyrimidine compounds, for the treatment of a disease or condition associated with tankyrase, e.g. cancer selected from e.g. breast, colon, stomach, and liver. WO2014087165-A1, 2014.

Nathubhai, A., Wood, P. J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2013. Design and discovery of 2‑arylquinazolin-4-ones as potent and selective inhibitors of tankyrases. ACS Medicinal Chemistry Letters, 4 (12), pp. 1173-1177.

Qu, X., Allan, A., Chui, G., Hutchings, T. J., Jiao, P., Johnson, L., Leung, W. Y., Li, P. K., Steel, G. R., Thompson, A. S., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2013. Hydrolysis of ibuprofenoyl-CoA and other 2-APA-CoA esters by human acyl-CoA thioesterases-1 and -2 and their possible role in the chiral inversion of profens. Biochemical Pharmacology, 86 (11), pp. 1621-1625.

Woon, E. C. Y., Sunderland, P. T., Paine, H. A., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2013. One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs. Bioorganic and Medicinal Chemistry, 21 (17), pp. 5218-5227.

Nathubhai, A., Patterson, R., Woodman, T. J., Sharp, H. E. C., Chui, M. T. Y., Chung, H. H. K., Lau, S. W. S., Zheng, J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2011. N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides. Organic and Biomolecular Chemistry, 9 (17), pp. 6089-6099.

Woodman, T. J., Wood, P. J., Thompson, A. S., Hutchings, T. J., Steel, G. R., Jiao, P., Threadgill, M. D. and Lloyd, M. D., 2011. Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)-a potential mechanism for the anti-cancer effects of ibuprofen. Chemical Communications, 47 (26), pp. 7332-7334.

Hopton, S. R. and Thompson, A. S., 2011. Nuclear magnetic resonance solution structures of inter- and intrastrand adducts of DNA cross-linker SJG-136. Biochemistry, 50 (21), pp. 4720-4732.

Hopton, S. R. and Thompson, A. S., 2011. Manipulative interplay of two adozelesin molecules with d(ATTAAT)2 achieving ligand-stacked Watson-Crick and Hoogsteen base-paired duplex adducts. Biochemistry, 50 (19), pp. 4143-4154.

Holbourn, K. P., Lloyd, M. D., Thompson, A. S., Threadgill, M. D. and Acharya, K. R., 2011. Cloning, purification, crystallization and preliminary crystallographic analysis of the human histone deacetylase sirtuin 1. Acta Crystallographica Section F-Structural Biology and Crystallization Communications, 67 (4), pp. 461-463.

Sunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor. Organic and Biomolecular Chemistry, 9 (3), pp. 881-891.

Sunderland, P. T., Woon, E. C. Y., Dhami, A., Bergin, A. B., Mahon, M. F., Wood, P. J., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. 5-benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2). Journal of Medicinal Chemistry, 54 (7), pp. 2049-2059.

Woodman, T.J., Wood, P. J., Thompson, A. S., Hutchings, T. J., Jiao, P., Steel, G. R., Threadgill, M. D. and Lloyd, M. D., 2011. Chiral inversion of NSAID-CoA esters by human ∝-methylacyl-CoA racemase. In: Cancer Research @ Bath Conference, 2011, 2011-05-01.

Rahman, K. M., Thompson, A. S., James, C. H., Narayanaswamy, M. and Thurston, D. E., 2009. The pyrrolobenzodiazepine dimer SJG-136 forms sequence-dependent intrastrand DNA cross-links and monoalkylated adducts in addition to interstrand cross-links. Journal of the American Chemical Society, 131 (38), pp. 13756-13766.

This list was generated on Thu Oct 19 12:54:32 2017 IST.

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