Design and biological evaluation of dual tubulin/HDAC inhibitors based on millepachine for treatment of prostate cancer

In this work, a novel of dual tubulin/HDAC inhibitors were designed and synthesized based on the structure of natural product millepachine, which has been identified as a tubulin polymerization inhibitor. Biological evaluation revealed that compound 9n exhibited an impressive potency against PC-3 cells with the IC₅₀ value of 16 nM and effectively inhibited both microtubule polymerization and HDAC activity. Furthermore, compound 9n not only induced cell cycle arrest at G2/M phase, but also induced PC- 3 cells Apoptosis. Further study revealed that the induction of cell Apoptosis by 9n was accompanied by a decrease in mitochondrial membrane potential and an elevation in Reactive Oxygen Species levels in PC-3 cells. Additionally, 9n exhibited inhibitory effects on tumor cell migration and angiogenesis. In PC-3 xenograft model, 9n achieved a remarkable tumor inhibition rate of 90.07%@20 mg/kg, significantly surpassing to that of CA-4 (55.62%@20 mg/kg). Meanwhile, 9n exhibited the favorable drug metabolism characteristics in vivo. All the results indicate that 9n is a promising dual tubulin/HDAC Inhibitor for chemotherapy of prostate Cancer, deserving the further investigation.

Antitumor; HDAC; Millepachine; Tubulin.