具有抗肿瘤活性的双取代芳酰胺类异羟肟酸基组蛋白去乙酰化酶抑制剂的研发。
Development of hydroxamate-based histone deacetylase inhibitors of bis-substituted aromatic amides with antitumor activities.
作者信息
Ge Di, Han Lina, Yang Feifei, Zhao Na, Yang Yang, Zhang Hua, Chen Yihua
机构信息
School of Biological Science and Technology , University of Jinan , Jinan , Shandong Province 250022 , China . Email:
Shanghai Key Laboratory of Regulatory Biology , The Institute of Biomedical Sciences and School of Life Sciences , East China Normal University , Shanghai , 200241 , China . Email:
出版信息
Medchemcomm. 2019 Aug 20;10(10):1828-1837. doi: 10.1039/c9md00306a. eCollection 2019 Oct 1.
Abstract
Previously, we designed and synthesized a series of bis-substituted aromatic amide-based histone deacetylase (HDAC) inhibitors. In this study, we report the replacement of a bromine atom by different amides on the phenyl ring of the CAP region. Representative compounds and exhibited low nanomolar IC values against HDAC1, which were ten times lower than that of the positive control SAHA. The IC of against the human A549 cancer cell line was 2.13 μM. Furthermore, increased the acetylation of histones H3 and H4 in a dose-dependent manner. Moreover, significantly arrested A549 cells at the G2/M phase and induced A549 cell apoptosis. Finally, molecular docking investigation rationalized the high potency of compound .
摘要
此前，我们设计并合成了一系列基于双取代芳族酰胺的组蛋白脱乙酰酶（HDAC）抑制剂。在本研究中，我们报道了在CAP区域的苯环上用不同的酰胺取代溴原子。代表性化合物 和 对HDAC1表现出低纳摩尔IC值，比阳性对照SAHA低十倍。 对人A549癌细胞系的IC为2.13 μM。此外， 以剂量依赖性方式增加组蛋白H3和H4的乙酰化。此外， 显著将A549细胞阻滞在G2/M期并诱导A549细胞凋亡。最后，分子对接研究解释了化合物 的高效力。
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