The Development of Novel Thieno[2,3-b]pyridine Derivatives as Potent PI-PLC Inhibitors: Synthesis, Docking, and Anti-proliferative Studies

Abstract

The creation of novel targeted therapies to treat cancer is one of the most challenging problems faced by medicinal chemists today. New drug candidates are ideally potent and selective, eliminating only cancer cells whilst leaving healthy cells alive, and thereby having minimal adverse effects. Therefore, the search for novel compounds that induce a targeted response in cells by inhibiting specific proteins is a valuable area of research. Phospholipases, an example of such proteins, are crucial for the regulation of cellular processes. The inhibition of the protein subtype phospholipase C by compounds known as thieno[2,3-b]pyridines has been an important area of study since 2009. Thieno[2,3-b]pyridine analogues have exhibited good antiproliferative activity against melanoma and colon cancer cell lines in previous studies. Therefore, the aim of this project turned to the further improvement of thieno[2,3-b]pyridine anti-proliferative activity by introducing previously unexplored functional groups on to the thieno[2,3-b]pyridine structural framework, with the aim of improving their activity. Multiple series of thieno[2,3-b]pyridines and their derivatives were synthesised in this work; N-phenylethyl thieno[2,3-b]naphthyridines, iso/quinoline and benzodioxane carboxamide thieno[2,3-b]pyridines/quinolines/naphthyridines, enone thieno[2,3-b]pyridines, saturated ketone thieno[2,3-b]pyridines, allylic alcohol thieno[2,3-b]pyridines, and ‘prodrug-like’ ester/carbonate thieno[2,3-b]pyridines to give a total of 127 new analogues. The analogues were examined using molecular modelling docking studies against the probable enzyme target phosphoinositide phospholipase C (PI-PLC) and were tested for their anti-proliferative activity against cancer cell lines HCT-116 and MDA-MB-231, with some analogues showing particularly potent biological activity, exhibiting IC₅₀ values in the nanomolar range. In particular, some analogues exhibited IC₅₀ values lower than 50 nM which was an improvement compared to previously synthesised thienopyridines. Separately, it was also shown this class of compound has no activity against bacteria and reduced activity versus yeast, highlighting their selectivity to human cell lines.