Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China.
Department of Pharmacy, Yiyang Central Hospital, Yiyang 413000, Hunan, China.
J Med Chem. 2020 May 14;63(9):4685-4700. doi: 10.1021/acs.jmedchem.9b02097. Epub 2020 Apr 27.
Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.
Apcin 是少数几种被报道为 Cdc20 特异性抑制剂的化合物之一，尽管 Cdc20 是一个很有前途的药物靶点。我们在这里报告了作为 Cdc20 抑制剂的 2,2,2-三氯-1-芳基氨基甲酸酯衍生物的设计、合成和生物学评价。在这些衍生物中，化合物 比阳性化合物 apcin 更有效地抑制癌细胞生长，但在 SPR 分析中它与 apcin 的结合亲和力大致相同。可能存在另一种作用机制。进一步的证据表明，化合物 还抑制微管蛋白聚合，扰乱微管网络，并通过细胞周期蛋白表达的变化将细胞周期阻滞在 M 期，从而通过激活 caspase-3 和 PARP 诱导细胞凋亡。此外，化合物 以浓度依赖的方式抑制细胞迁移和侵袭。这些结果为开发当前系列作为潜在的新型抗癌治疗药物提供了指导。
