Synthesis and Investigation of Anti-proliferative Thieno[2,3-b]pyridine Derivatives with Enhanced Solubility

Abstract

Phospholipases are important regulators of cellular processes, in particular the PLC-δ (phospholipase C-delta) isoform has been identified as being involved in cellular processes directly involved in cancer progression. Therefore, the design of compounds to inhibit PLC-δ has become a viable target for anticancer therapy. A number of compounds have been identified within the thienopyridine family that have shown good anti-proliferative activity in cancer cell lines HCT-116 and MDA-MB-231, but their practicality as potential drugs is limited by their poor solubility. The aim of this project was to prepare novel analogues of thienopyridines that contain the known successful characteristics of the previous compounds and introduce new functional groups that would improve the solubility, all whilst maintaining good anti-proliferative activity. Seven different series of thieno[2,3-b]pyridine derivatives were synthesised; the pyrrolo[2,3- b]quinolones, 5-acetyl-6-methylthieno[2,3-b]pyridines, 5-(1-hydroxyethyl)-6- methylthieno[2,3-b]pyridines, N-benzyl thieno[2,3-b]naphthyridines, N-methyl thieno[2,3- b]naphthyridines, pyrano[4,3-b]thieno[3,2-e]pyridines and other thieno[2,3-b]pyridine derivatives to give a total of 49 new analogues. The compounds were then examined using molecular modelling docking studies, followed by biological testing at the Auckland Cancer Society Research Centre (ACSRC) and the National Cancer Institute (NCI). These studies enabled comparisons between the modelling scores and their biological activity to be made. This allowed for an improved structure-activity relationship (SAR) in this family of compounds, introducing descriptors allowing improved solubility. A number of highly bioactive compounds were discovered that, additionally, had improved solubility compared to previous analogues, specifically compounds 19b and 19e. These compounds had IC50 values in the low nanomolar range - the lowest recorded for the known thienopyridine derivatives.