School of Pharmaceutical Sciences, Nanchang University, Nanchang 330006, China.
School of Pharmaceutical Sciences, Nanchang University, Nanchang 330006, China.
Bioorg Med Chem. 2022 Feb 15;56:116599. doi: 10.1016/j.bmc.2021.116599. Epub 2021 Dec 31.
The aminobenzamide is selective to class I histone deacetylases (HDACs) and displays unique tight-binding/slow-off HDAC-binding mechanism. Herein, we report a series of 9-substituted purine aminobenzamides that selectively inhibit class I HDACs. The activities in vitro showed compound 9d exhibited 12 folds more potent than MS-275 against HDAC1 isoform and showed excellent inhibitory activity on cancer cells, including HCT-116, MDA-MB-231, K562 cell lines. The metabolic stability of 9d was much better than that of the well-known HDAC inhibitor SAHA. Pulse exposure test of western blot assay demonstrated that 9a, 9d induced histone acetylation in a similar manner to MS-275. Further biological validation demonstrated that 9d prevented cell transition from G1 phase to S phase by reducing Cyclin D1, CDK2 and lifting p21, induced early apoptosis by upregulating BAX and downregulating Bcl-2 in HCT-116 cells.
氨甲酰胺对 I 类组蛋白去乙酰化酶（HDACs）具有选择性，并表现出独特的紧密结合/缓慢释放的 HDAC 结合机制。在此，我们报告了一系列 9-取代嘌呤氨甲酰胺，它们选择性地抑制 I 类 HDAC。体外活性研究表明，化合物 9d 对 HDAC1 同工型的抑制活性比 MS-275 强 12 倍，对包括 HCT-116、MDA-MB-231、K562 细胞系在内的癌细胞具有优异的抑制活性。9d 的代谢稳定性明显优于知名的 HDAC 抑制剂 SAHA。Western blot 检测的脉冲暴露试验表明，9a、9d 以类似于 MS-275 的方式诱导组蛋白乙酰化。进一步的生物学验证表明，9d 通过降低 Cyclin D1、CDK2 和上调 p21，将细胞从 G1 期阻滞到 S 期，通过上调 BAX 和下调 Bcl-2 在 HCT-116 细胞中诱导早期凋亡。
