Greaney, Michael

Hulme, Alison

Clipson, Alexandra Jayne

Cancer Research UK

2014-11-21T15:22:24Z

2014-11-21T15:22:24Z

2012-06-22

Target-guided synthesis is an approach to drug discovery that uses the biological target as a template to direct synthesis of its own best inhibitors from small molecule fragments. The process bridges the gap between chemical synthesis of drug candidates and their biological binding assay, merging the two operations into a single process whereby the active site or a binding pocket within the structure of the biological target directly controls the assembly of the best inhibitor in situ. Two different approaches to target-guided synthesis, the thermodynamic approach, making use of reversible reactions, and the kinetic approach, which uses an irreversible reaction, have been employed to discover novel, isoform selective inhibitors of the glutathione transferase (GST) enzyme family – possible drug targets in cancer and parasitic disease treatments. The thermodynamic approach described in this thesis uses the aniline-catalysed reversible acyl hydrazone formation reaction to create a dynamic covalent library of bivalent ligands designed to bind the dimeric structure of GST. In the presence of GST one of the bivalent ligands was selectively amplified at the expense of the other library members. This ligand was shown, via biological assays, to be a specific inhibitor for one isoform of GST, the mu isoform mGSTM1-1. A kinetic approach has also been investigated as a way to identify novel bivalent GST inhibitors utilising the Huisgen 1, 3 dipolar cycloaddition reaction. An azide and alkyne fragment library was designed to bind across the dimeric GST structure. The inhibitor structures are therefore bivalent, containing two anchoring fragments known to bind to the GST active site, linked by a triazolopeptide spacer. The triazole provides the click chemistry disconnection, enabling rapid in situ screening of candidate alkyne and azide fragments for inhibitor discovery. Whilst the in situ reaction with GST yielded inconclusive results, a number of the triazole products were found to have low nanomolar inhibitory activity towards GST.

http://hdl.handle.net/1842/9704

en

The University of Edinburgh

dynamic combinatorial chemistry

In situ click chemistry

glutathione transferases

Target-guided synthesis approach to the discovery of novel bivalent inhibitors of Glutathione Transferases

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy