Development of 3-hydroxycinnamamide-based HDAC inhibitors with potent in vitro and in vivo anti-tumor activity

被引：15

作者：

Li, Xiaoyang ^{[1
]}

Hou, Jinning ^{[1
]}

Li, Xiaoguang ^{[1
]}

Jiang, Yuqi ^{[1
]}

Liu, Xueliang ^{[1
]}

Mu, Weiwei ^{[1
]}

Jin, Yiming ^{[1
]}

Zhang, Yingjie ^{[1
]}

Xu, Wenfang ^{[1
]}

机构：

[1] Shandong Univ, Sch Pharm, Dept Med Chem, Jinan 250012, Shandong, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 89卷

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

HDACs; HDACIs; Anti-tumor drugs; Antiproliferative activity; In vivo oral activity; HISTONE DEACETYLASE INHIBITORS; CANCER; MECHANISMS; THERAPY;

D O I：

10.1016/j.ejmech.2014.10.077

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of histone deacetylases (HDACs) has diverse effects on cell function, such as causing differentiation, growth arrest and apoptosis in nearly all types of tumor cell lines. In our previous work, we have designed and synthesized a novel series of 4-hydroxycinnamamide-based and 3-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which, 3-hydroxycinnamamide-based HDACIs 1a-1c exhibited moderate inhibition against HDACs. In this article, we report the development of a more potent class of 3-hydroxycinnamamide-based HDACIs, compound 7o exhibited much higher pan-HDAC inhibitory activity than positive control SAHA. In addition, compound 7h showed excellent in vitro growth inhibitory activity against more than ten cell lines and induced U937 cells apoptosis in micromolar concentration. In vivo assay in U937 xenograft model identified compound 7h as a potent, orally active HDACI. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：628 / 637

页数：10

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