Synthesis and biological evaluation of 2,3-diarylthiophene analogues of combretastatin A-4

Abstract

A series of novel 2,3-diarylthiophene analogues of combretastatin A-4 (CA-4) were designed with a rigid thiophene moiety to retain the cis-olefin configuration of CA-4 and were subsequently synthesised. All of the target compounds were evaluated for their in vitro anti-proliferative activities. Among these compounds, 5f and 8d exhibited superior potency against different tumour cell lines with IC₅₀ values at sub-micromolar levels. Moreover, compound 8d significantly inhibited tubulin polymerisation to microtubules and caused microtubule destabilisation. In addition, a molecular modelling study of compound 8d was performed to clarify its binding mode at the colchicine site in the tubulin dimer and to provide a basis for further structure-guided design of novel CA-4 analogues.