Hybridization of the Pharmacophoric Features of Discoipyrrole C and Combretastatin A‐4 toward New Anticancer Leads

Abstract

Pharmacophore hybridization is an attractive strategy to identify new leads against multifactorial diseases such as cancer. Based on literature analysis of compounds possessing ‘vicinal diaryl’ fragment in their structure, we considered Discoipyrroles A−D and Combretastatin A‐4 (CA‐4) as possible components in hybrid design. Discoipyrrole C (Dis C) and CA‐4 were used as reference compounds in these studies and their hybrids, in the form of 4,5‐diaryl‐1H‐pyrrol‐3(2H)‐ones, were synthesized from suitable amino acid precursors though their ynone intermediates. Of these, the hybrid having exact substitution pattern as that of CA‐4 showed better potency and selectivity than Dis C, but its activity was less compared to CA‐4. This new analog disrupted interphase microtubules by inhibiting tubulin assembly by binding to the colchicine site, induced multipolar spindles, caused cell cycle block and apoptosis in HeLa cells. It also inhibited colony formation and migration of breast cancer cell lines.