Design, synthesis, and biological evaluation of 1, 3-disubstituted-pyrazole derivatives as new class I and IIb histone deacetylase inhibitors

Yiwu Yao; Chenzhong Liao; Zheng Li; Zhen Wang; Qiao Sun; Chunping Liu; Yang Yang; Zhengchao Tu; Sheng Jiang

doi:10.1016/j.ejmech.2014.09.024

Design, synthesis, and biological evaluation of 1, 3-disubstituted-pyrazole derivatives as new class I and IIb histone deacetylase inhibitors

Eur J Med Chem. 2014 Oct 30:86:639-52. doi: 10.1016/j.ejmech.2014.09.024. Epub 2014 Sep 8.

Authors

Yiwu Yao¹, Chenzhong Liao², Zheng Li³, Zhen Wang¹, Qiao Sun¹, Chunping Liu¹, Yang Yang², Zhengchao Tu⁴, Sheng Jiang⁵

Affiliations

¹ Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
² School of Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, China.
³ The Methodist Hospital Research Institute, Houston, TX 77030, USA.
⁴ Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: tu_zhengchao@gibh.ac.cn.
⁵ Laboratory of Medicinal Chemistry, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China. Electronic address: jiang_sheng@gibh.ac.cn.

PMID: 25218912
DOI: 10.1016/j.ejmech.2014.09.024

Abstract

A novel series of HDAC inhibitors demonstrating class I and IIb subtype selectivity have been identified using a scaffold-hopping strategy. Several designed compounds showed better selectivity for class I and IIb over class IIa HDAC isoforms comparing to the FDA approved HDAC targeting drug SAHA. A representative lead compound 22 bearing a biphenyl moiety demonstrated promising class I and IIb HDAC isoforms selectivity and in vitro anticancer activities against several cancer cell lines. This work could serve as a fundamental platform for further exploration of selective HDAC inhibitors using designed molecular scaffold.

Keywords: HDAC; Isoforms selectivity; Scaffold-hopping; Structure–activity relationship.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
HeLa Cells
Histone Deacetylase 1 / antagonists & inhibitors*
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / antagonists & inhibitors*
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
K562 Cells
MCF-7 Cells
Models, Molecular
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
U937 Cells

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Pyrazoles
pyrazole
Histone Deacetylase 1
Histone Deacetylase 2