Discovery of pyrimidine-bridged CA-4 CBSIs for the treatment of cervical cancer in combination with cisplatin with significantly reduced nephrotoxicity
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A series of pyrimidine-bridged CA-4 derivatives (9a-u) targeting colchicine site were designed, synthesized and evaluated. Among them, the most potent compound 9j showed favorable anti-proliferative activities against a panel of cervical cancer cells (IC50 = 0.09–0.15 μM) and tubulin polymerization inhibitory activity (IC50 = 4.6 μM). Meanwhile, compound 9j exhibited superior anti-proliferative activity against cisplatin-resistant HeLa/DDP and SiHa/DDP cells than CA-4 and cisplatin. Particularly, the combination of 30 mg/kg 9j with 3 mg/kg cisplatin resulted in a 73% tumor suppression rate in HeLa xenograft model and reduced the renal dysfunction and injuries caused by high doses of cisplatin. Moreover, 9j was highly selective over the normal human proximal tubular cells (HK-2 cells, IC50 = 188 μM). Mechanism studies revealed that 9j could disrupt tubulin polymerization and vasculature, arrest the cell cycle at the G2/M phase, induce apoptosis, and suppress clonogenesis and migration in HeLa cells. Further druggability characterization in terms of pharmacokinetic profile, acute toxicity, and hERG inhibition confirmed 9j could serve as a promising and safe combination agent for cervical cancer therapy.