Discovery of Novel Furan-type Phenylahistin Derivatives for Anticancer through P53-Mediated Mitochondrial Apoptosis and Microtubule Inhibition

Tubulin inhibitors, such as taxanes and vinca alkaloids, target the microtubule and are limited by multidrug resistance, toxicity, and myelosuppression. Phenylahistin derivatives, a natural marine product, exert an anticancer effect by depolymerizing microtubules and disrupting vasculature and treat chemotherapy-induced neutropenia by activating GEF-H1, which binds to the colchicine site. To discover new phenylahistin derivatives, 24 novel furan-type phenylahistin derivatives were designed and synthesized by replacing the 1,3-imidazol-4-yl group with furan-type substitutions. Antitumor proliferation screening showed that <b>10u</b> (16 nM) and <b>10v</b> (21 nM) were more effective than plinabulin (26 nM). Compounds <b>10u</b> and <b>10v</b> induced cell death through the mitochondrial pathway. Compounds <b>10u</b> and <b>10v</b> also induced cancer cell apoptosis by inhibiting Bcl-2, upregulating P53, reducing mitochondrial membrane potential, and elevating ROS levels, disrupting microtubule networks, inducing G2/M arrest, and promoting apoptosis via caspase-3 activation. And molecular docking revealed that the furan-based derivatives formed important bonds with β-tubulin.