Design and synthesis of biaryl aryl stilbenes/ethylenes as antimicrotubule agents

Two new series of compounds E-2,3,4-trimethoxy-6-styrylbiphenyls and 2,3,4-trimethoxy-6-(1-phenylvinyl)biphenyls were designed, synthesized and evaluated for antitubulin activity. A common intermediate 4,5,6-trimethoxybiphenyl-2-carbaldehydes was employed to generate the two scaffolds. Majority of the analogs inhibited cell proliferation and those functionalized with 3,4-(1,3-dioxolane) and 3,4-difluoro groups were identified as effective inhibitors in both the series. Treatments with 19b, 19c, 22b and 22c arrested cells at G2/M phase, disrupted microtubule network, accumulated tubulin in the soluble fraction and manifested an increased expression of the G2/M marker, Cyclin B1. Molecular docking analysis demonstrated the interaction of these compounds at the colchicine binding site of tubulin.

Graphical abstractTwo new series of compounds E-2,3,4-trimethoxy-6-styrylbiphenyls and 2,3,4-trimethoxy-6-(1-phenylvinyl)biphenyls were designed, synthesized and evaluated for antitubulin activity. Effective compounds interacted at colchicine binding site of tubulin.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Twenty two biaryl aryl stilbenes/ethylenes were designed and synthesized. ► Most of the compounds inhibited cell proliferation against 4 cancer cell lines. ► Potent derivatives arrested cells at G2/M phase, disrupted microtubule network. ► Investigated compounds dock at the colchicine binding site of the tubulin.