School of Pharmacy, Fudan University, Shanghai 201203, China.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Bioorg Med Chem. 2023 Sep 7;92:117437. doi: 10.1016/j.bmc.2023.117437. Epub 2023 Aug 2.
Tubulin and histone deacetylase have been clinically proven as promising targets for cancer therapy. Herein, we describe the design and synthesis of chiral 1,4-diarylazetidin-2-one-based hydroxamic acids as novel tubulin/HDAC dual inhibitors. Among them, compound 12a was validated to effectively disrupt tubulin polymerization, and exhibited potent HDAC1/8 inhibitory activities. Meanwhile, 12a showed good antiproliferative activities against four tumor cell lines. Further studies showed 12a works through blocking cellular cycle, inducing apoptosis and inhibiting colony formation. In addition, 12a has suitable physicochemical properties and high liver microsomal metabolic stability. Importantly, compound 12a was found to exhibit significant antitumor efficacy in vivo, thus warranting it as a promising tubulin/HDAC dual inhibitor for further development.
微管蛋白和组蛋白去乙酰化酶已被临床证明是癌症治疗有前途的靶点。本文描述了手性 1,4-二芳基氮杂环丁酮基羟肟酸作为新型微管蛋白/HDAC 双重抑制剂的设计和合成。其中，化合物 12a 被证实可有效破坏微管蛋白聚合，并表现出强烈的 HDAC1/8 抑制活性。同时，12a 对四种肿瘤细胞系表现出良好的增殖抑制活性。进一步的研究表明，12a 通过阻断细胞周期、诱导细胞凋亡和抑制集落形成发挥作用。此外，12a 具有适宜的理化性质和较高的肝微粒体代谢稳定性。重要的是，在体内研究中发现化合物 12a 具有显著的抗肿瘤疗效，因此有望成为一种有前途的微管蛋白/HDAC 双重抑制剂，进一步开发。
