当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy.

Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy.

Abstract：

:In this study, a collection of N-(6-mercaptohexyl)-3-substituted-1H-pyrazole-5-carboxamide HDAC inhibitors was developed. Among them, 15k was identified as the most potent inhibitor against total HDACs with IC50 of 0.008 μM. Further isoenzyme assays revealed that 15k and its analogs have a preference for HDAC1-3 (class I) and HDAC6 (class IIb) isoforms. The enzyme-based potencies of 15k were 2- to 11-fold higher than those of Vorinostat. The disulfide prodrug 18 was found to be potent cytotoxic agent against a panel of seven tumor cells, causing hyper-acetylation of histone and non-histone proteins in cellular level. In addition, 18 demonstrated a notable in vivo anti-tumor activity in HCT-116 xenografted model. This study provides further possibility of developing novel thiol-based HDAC inhibitors for the treatment of cancer.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Wen J,Bao Y,Niu Q,Yang J,Fan Y,Li J,Jing Y,Zhao L,Liu D

doi

10.1016/j.ejmech.2016.01.013

subject

Has Abstract

pub_date

2016-02-15 00:00:00

pages

350-9

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30013-7

journal_volume

109

pub_type

杂志文章

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