Abstract

A series of 7,8-dihydroxy-4-arylcoumarins, the derivatives related to DW532 that was an anti-tumor agent targeting both kinase and tubulin, was prepared by Suzuki coupling reaction. Among them, compounds 6a, 6b, and 6c were found to exhibit anti-proliferation activities against human breast carcinoma MDA-MB-468 cells with IC₅₀ values of 0.64, 0.69, and 1.33 μM, respectively and human epidermoid carcinoma A431 cells with IC₅₀ values of 2.56, 1.78, and 2.29 μM, respectively. Further evaluation of the selected molecules revealed that they displayed broad-spectrum inhibitory activities against a panel of kinases including Flt-1, VEGFR2, RET, EGFR, etc. In vitro tubulin polymerization assay and molecular docking indicated that the substitution of 3’-OH and 4’-OCH3 on the 4-phenyl ring was essential to achieve potent tubulin inhibition.

Keywords: Anticancer, 4-Arylcoumarin, Cytotoxicity, Structure-activity relationship, Tubulin, Tyrosine kinase inhibition.

Graphical Abstract