Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China.
Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China.
Eur J Med Chem. 2020 Mar 1;189:112073. doi: 10.1016/j.ejmech.2020.112073. Epub 2020 Jan 21.
In the current study, we reported a series of novel 1-H-pyrazole-3-carboxamide-based inhibitors targeting histone deacetylase (HDAC) and cyclin-dependent kinase (CDK). The representative compounds N-(4-((2-aminophenyl)carbamoyl)benzyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (7c) and N-(4-(2-((2-aminophenyl)amino)-2-oxoethyl)phenyl)-4-(2,6-dichlorobenzamido)-1H-pyrazole-3-carboxamide (14a) with potent antiproliferative activities towards five solid cancer cell lines, showed excellent inhibitory activities against HDAC2 (IC = 0.25 and 0.24 nM respectively) and CDK2 (IC = 0.30 and 0.56 nM respectively). In addition, compounds 7c and 14a significantly inhibited the migration of A375 and H460 cells. Further studies revealed that compounds 7c and 14a could arrest cell cycle in G2/M phase and promote apoptosis in A375, HCT116, H460 and Hela cells, which was associated with increasing the intracellular reactive oxygen species (ROS) levels. More importantly, compound 7c possessed favorable pharmacokinetic properties with the intraperitoneal bioavailability of 63.6% in ICR mice, and potent in vivo antitumor efficacy in the HCT116 xenograft model. Our study demonstrated that compound 7c provides a promising strategy for the treatment of malignant tumors.
在当前的研究中，我们报道了一系列新型 1-H-吡唑-3-甲酰胺类组蛋白去乙酰化酶（HDAC）和细胞周期蛋白依赖性激酶（CDK）抑制剂。代表性化合物 N-(4-((2-氨基苯基)氨基甲酰基)苄基)-4-(2,6-二氯苯甲酰胺基)-1H-吡唑-3-甲酰胺（7c）和 N-(4-(2-((2-氨基苯基)氨基)-2-氧代乙基)苯基)-4-(2,6-二氯苯甲酰胺基)-1H-吡唑-3-甲酰胺（14a）对五种实体癌细胞系具有很强的增殖抑制活性，对 HDAC2（IC=0.25 和 0.24 nM 分别）和 CDK2（IC=0.30 和 0.56 nM 分别）具有优异的抑制活性。此外，化合物 7c 和 14a 显著抑制了 A375 和 H460 细胞的迁移。进一步的研究表明，化合物 7c 和 14a 可以使 A375、HCT116、H460 和 Hela 细胞的细胞周期停滞在 G2/M 期，并促进细胞凋亡，这与细胞内活性氧（ROS）水平的增加有关。更重要的是，化合物 7c 具有良好的药代动力学特性，在 ICR 小鼠中腹腔生物利用度为 63.6%，在 HCT116 异种移植模型中具有很强的体内抗肿瘤疗效。我们的研究表明，化合物 7c 为恶性肿瘤的治疗提供了一种有前景的策略。
