Pt(IV) prodrugs containing microtubule inhibitors displayed potent antitumor activity and ability to overcome cisplatin resistance.

It is well-known that cisplatin exhibited a broad spectrum of anticancer activities against many solid tumors, but its severe toxicity and drug resistance have largely limited wider clinical applications. Various strategies have been tried to discover new Pt (II) drugs with at least equal activity as well as low toxicity compared to cisplatin, but the inherent problem remains unsolved. Here we report that Pt (IV) complexes comprising a CA-4 analogue, as dual-targeting Pt (IV) prodrug, were synthesized and evaluated for anti-proliferative activity using MTT assay. Among them, complex 19 displayed most potent activity against the tested cancer cell lines, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than that of cisplatin. Mechanism studies revealed that complex 19 effectively induced cell cycle arrest at the G2/M phase and dramatically disrupted the microtubule organization. Moreover, complex 19 significantly induced cell apoptosis and decreased MMP. Importantly, complex 19 significantly inhibited tumor growth in SK-OV-3 xenograft model in vivo without apparent toxicity.