Design, synthesis and biological evaluation of bisthiazole-based trifluoromethyl ketone derivatives as potent HDAC inhibitors with improved cellular efficacy

Chao-Jun Gong; An-Hui Gao; Yang-Ming Zhang; Ming-Bo Su; Fei Chen; Li Sheng; Yu-Bo Zhou; Jing-Ya Li; Jia Li; Fa-Jun Nan

doi:10.1016/j.ejmech.2016.02.003

Design, synthesis and biological evaluation of bisthiazole-based trifluoromethyl ketone derivatives as potent HDAC inhibitors with improved cellular efficacy

Eur J Med Chem. 2016 Apr 13:112:81-90. doi: 10.1016/j.ejmech.2016.02.003. Epub 2016 Feb 4.

Authors

Chao-Jun Gong¹, An-Hui Gao¹, Yang-Ming Zhang¹, Ming-Bo Su¹, Fei Chen¹, Li Sheng¹, Yu-Bo Zhou¹, Jing-Ya Li¹, Jia Li², Fa-Jun Nan³

Affiliations

¹ Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, PR China.
² Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, PR China. Electronic address: jli@simm.ac.cn.
³ Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, PR China. Electronic address: fjnan@simm.ac.cn.

PMID: 26890114
DOI: 10.1016/j.ejmech.2016.02.003

Abstract

Histone deacetylases (HDACs) are a class of epigenetic modulators with complex functions in histone post-translational modifications and are well known targets for antineoplastic drugs. We have previously developed a series of bisthiazole-based hydroxamic acids as novel potent HDAC inhibitors. In the present work, a new series of bisthiazole-based compounds with different zinc binding groups (ZBGs) have been designed and synthesized. Among them is compound 7, containing a trifluoromethyl ketone as the ZBG, which displays potent inhibitory activity towards human HDACs and improved antiproliferative activity in several cancer cell lines.

Keywords: Bisthiazole; Histone deacetylases; Trifluoromethyl ketones; ZBG.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
Halogenation
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Humans
Ketones / chemical synthesis
Ketones / chemistry
Ketones / pharmacology
Methylation
Neoplasms / drug therapy
Neoplasms / enzymology
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology*
Zinc / metabolism

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Ketones
Thiazoles
Zinc