Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity

Wenwen Duan; Jinning Hou; Xiaojing Chu; Xiaoqian Li; Jian Zhang; Jin Li; Wenfang Xu; Yingjie Zhang

doi:10.1016/j.bmc.2015.06.015

Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity

Bioorg Med Chem. 2015 Aug 1;23(15):4481-4488. doi: 10.1016/j.bmc.2015.06.015. Epub 2015 Jun 20.

Authors

Wenwen Duan¹, Jinning Hou¹, Xiaojing Chu², Xiaoqian Li³, Jian Zhang⁴, Jin Li¹, Wenfang Xu¹, Yingjie Zhang⁵

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
² Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong 261061, People's Republic of China.
³ Color Ultrasonic Room, The People's Hospital of Shouguang, Weifang, Shandong 262700, People's Republic of China.
⁴ Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, West Baotong Street, Weifang, Shandong 261053, People's Republic of China.
⁵ Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China. Electronic address: [email protected].

PMID: 26122774
DOI: 10.1016/j.bmc.2015.06.015

Abstract

A novel series of histone deacetylases inhibitors (HDACIs) containing benzofuroxan pharmacophore as nitric oxide (NO) donor were designed based on the combination principle and 'multifunctional drugs' theory. As a novel study on embedding NO donor into the structure of HDACIs, all designed hybrid compounds, especially 19d and 24d, displayed remarkable HDACs inhibitory activity and outstanding antiproliferative activity on tumor cells. Besides, they could produce high levels of NO in HCT-116 cells; furthermore, their antiproliferative activity on HCT-116 cells could be diminished by pretreatment with hemoglobin, as the NO scavenger, in a dose-dependent manner. All in all, our designed compounds displayed great inhibitory activities and might offer a prospective avenue to discover novel anti-cancer drugs.

Keywords: Benzofuroxan; Epigenetic; HDAC inhibitor; Multifunctional drugs; Nitric oxide.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / toxicity
Benzoxazoles / chemical synthesis
Benzoxazoles / chemistry
Benzoxazoles / toxicity
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
HCT116 Cells
Hemoglobins / antagonists & inhibitors
Hemoglobins / metabolism
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / toxicity
Histone Deacetylases / chemistry*
Histone Deacetylases / metabolism
Humans
Nitric Oxide / metabolism*
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry
Oxadiazoles / toxicity

Substances

Antineoplastic Agents
Benzoxazoles
Hemoglobins
Histone Deacetylase Inhibitors
Oxadiazoles
Nitric Oxide
benzofuroxan
Histone Deacetylases