Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-b]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC

Natalie A Haverkate,Euphemia Leung,Lisa I Pilkington,David Barker

doi:10.3390/pharmaceutics13122020

Abstract

The compounds 2-amino-3-carboxamido-thieno[2,3-b]pyridines have demonstrated excellent anti-proliferative activity against human cancer cell lines, including the triple-negative breast cancer cell line MDA-MB-231. In this study, 81 novel thieno[2,3-b]pyridines were synthesised in four series to further improve their anti-proliferative activity, in particular by targeting an adjacent lipophilic pocket in the putative target enzyme phosphoinositide phospholipase C (PI-PLC). Overall, it was found that appending a propyl-aryl group at C-5 on 2-amino-3-carboxamido-thieno[2,3-b]pyridine resulted in compounds with potent biological activity, exhibiting IC50 values in the nanomolar range. The propyl linker could be an α,β-unsaturated ketone or a saturated propyl ketone, but the highest activity was obtained when allylic alcohols were the tether between thieno[2,3-b]pyridine and the appended aryl group, with compound 21r having IC50 values lower than 50 nM. Compounds with one extra carbon in the tether (i.e., a four-atom chain) were found to be considerably less active. Molecular modelling revealed this propyl tether places the newly introduced aryl ring in an untargeted lipophilic pocket within the active site of the phosphoinositide phospholipase C (PI-PLC) enzyme.

Highlights

The anti-proliferative thieno[2,3-b]pyridines have been extensively described in the literature, from their discovery in 2009 as potential inhibitors of phosphoinositide phospholipase C (PI-PLC) [1] to the more recent analogue series that have exhibited increasingly potent anti-proliferative activity against triple-negative breast cancer cell lines, with IC50 values in the nM range, inducing excellent cell growth inhibition
The purpose of the first series investigated in this work was to explore the theoretical size limit of the thienopyridines and ascertain whether moving the lipophilic aromatic ring further from the thienopyridine core would result in diminished, similar or improved biological activity. This resulted in the proposed synthesis of novel N-phenylethyl thieno[2,3-b]naphthyridine compounds, whichsynthesis are longer the
This study focused on the preparation of novel thieno[2,3-b]pyridines with additional tethered aryl groups reaching into a lipophilic pocket within the PI-PLC active site

Summary

Introduction

The anti-proliferative thieno[2,3-b]pyridines have been extensively described in the literature, from their discovery in 2009 as potential inhibitors of PI-PLC [1] to the more recent analogue series that have exhibited increasingly potent anti-proliferative activity against triple-negative breast cancer cell lines, with IC50 values in the nM range, inducing excellent cell growth inhibition. These findings have increased the interest in these compounds for the development of anti-cancer drugs [2,3,4]. This was corroborated by biological studies that showed that the knockdown of PLC-δ1 and δ3 isoforms in MDA-MB-231 cells had similar effects on cell morphology [6]

Methods

Results

Conclusion