2. Academic Validation
  3. Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study

Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study

  • Eur J Med Chem. 2017 Jul 7:134:185-206. doi: 10.1016/j.ejmech.2017.03.069.
Xiaoyang Li 1,  Yingjie Zhang 2,  Yuqi Jiang 3,  Jingde Wu 3,  Elizabeth S Inks 4,  C James Chou 4,  Shuai Gao 3,  Jinning Hou 3,  Qinge Ding 3,  Jingyao Li 3,  Xue Wang 3,  Yongxue Huang 5,  Wenfang Xu 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China; Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji'nan, Shandong, 250012, PR China. Electronic address: zhangyingjie@sdu.edu.cn.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.
  • 4 Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, SC, 29425, United States.
  • 5 Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, 261061, PR China.
PMID: 28415009 DOI: 10.1016/j.ejmech.2017.03.069
Abstract

Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency. Compound 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In vivo studies revealed that compound 11a displayed potent oral antitumor activity in both hematological tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and phenyl compounds (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine containing compound 56, with moderate HDAC3 selectivity.

Keywords

Anti-tumor drugs; Benzamides; HDACIs; HDACs; In vivo oral activity.

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