Abstract:
The membrane bound protein phospholipase is an important enzyme family that mediate intracellular and intercellular signalling pathways. The isoform phospholipase C gamma (PLC-γ) is involved in cell processes such as cell proliferation and motility, and is a viable target for anticancer treatments. However, up to now only a small number of inhibitors have been discovered, and none of them target specifically the PLC-γ isoform. Recently Reynisson et. al. and Feng et. al. reported the discovery of potential PLC-γ inhibitiors, the thieno[2,3-b]pyridine- 3-amine-derivatives, through a virtual high throughput screening (vHTS) approach, with the most potent inhibitor having LC50 down to 0.9 μM for the cell line MDA-MB-435 (breast cancer). This thesis describes the synthesis of analogues extending from the thieno[2,3- b]pyridine-3-amine-derivatives, aiming to further increase their PLC-γ inhibition activity. We successfully synthesised six different analogue series, thieno- and furopyridine-2-carboxamides, triazinone and pyrimidinone analogues, 5-oxo-tetrahydrothieno[2,3-b]quinoline-2-carboxamides and 5-hydroxy-tetrahydrothieno[2,3-b]quinoline-2-carboxamides. With the assistance of molecular modelling using four algorithms Piecewise Linear Potential (PLP/ChemPLP), GoldScore, ChemScore and Astex Statistical Potential (ASP), the binding interactions between the PLC active site and the thieno[2,3-b]pyridine-3-amine-derivatives were studied. A total of 46 compounds were selected and sent to the National Cancer Institute (NCI) for biological testing, and the structure-activity relationship (SAR) for thieno[2,3-b]pyridine-3-amine-derivatives was significantly advanced. These results have allowed further correlation between molecular modelling and experimental biological results, which will allow improved ligand design through computational methods.