Development of hydroxamate-based histone deacetylase inhibitors of bis-substituted aromatic amides with antitumor activities

Di Ge; Lina Han; Feifei Yang; Na Zhao; Yang Yang; Hua Zhang; Yihua Chen

doi:10.1039/c9md00306a

Development of hydroxamate-based histone deacetylase inhibitors of bis-substituted aromatic amides with antitumor activities

Medchemcomm. 2019 Aug 20;10(10):1828-1837. doi: 10.1039/c9md00306a. eCollection 2019 Oct 1.

Authors

Di Ge¹, Lina Han¹, Feifei Yang^{1

2}, Na Zhao¹, Yang Yang², Hua Zhang¹, Yihua Chen²

Affiliations

¹ School of Biological Science and Technology , University of Jinan , Jinan , Shandong Province 250022 , China . Email: yee68511@126.com ; Email: bio_zhangh@ujn.edu.cn.
² Shanghai Key Laboratory of Regulatory Biology , The Institute of Biomedical Sciences and School of Life Sciences , East China Normal University , Shanghai , 200241 , China . Email: yhchen@bio.ecnu.edu.cn.

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 9d and 10k exhibited low nanomolar IC₅₀ values against HDAC1, which were ten times lower than that of the positive control SAHA. The IC₅₀ of 9d against the human A549 cancer cell line was 2.13 μM. Furthermore, 9d increased the acetylation of histones H3 and H4 in a dose-dependent manner. Moreover, 9d significantly arrested A549 cells at the G2/M phase and induced A549 cell apoptosis. Finally, molecular docking investigation rationalized the high potency of compound 9d.