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 10u (16 nM) and 10v (21 nM) were more effective than plinabulin (26 nM). Compounds 10u and 10v induced cell death through the mitochondrial pathway. Compounds 10u and 10v 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.

Anticancer; Microtubulin Inhibition; P53 Induction; Phenylahistin; Structure-based.