Design, synthesis and in vitro evaluation of amidoximes as histone deacetylase inhibitors for cancer therapy

被引：7

作者：

Jiao, Peifu ^{[1
]}

Jin, Peng ^{[1
]}

Li, Chencan ^{[1
]}

Cui, Lechao ^{[1
]}

Dong, Lihua ^{[1
]}

Pan, Bin ^{[3
]}

Song, Wentong ^{[3
]}

Ma, Liang ^{[3
]}

Dong, Jinlong ^{[1
]}

Song, Lei ^{[1
]}

Jin, Xinjie ^{[1
]}

Li, Faming ^{[1
]}

Wan, Maosheng ^{[2
]}

Lv, Zhitao ^{[3
]}

Geng, Qiaohong ^{[1
]}

机构：

[1] Qilu Normal Univ, Dept Chem, Jinan 250200, Shandong, Peoples R China

[2] Hezhou Univ, Sch Chem & Biol Engn, Hezhou 542899, Guangxi, Peoples R China

[3] Shandong Chengchuang Pharmaceut R&D Co Ltd, Jinan 250101, Shandong, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 19期

关键词：

Amindoximes; HDACs; Cytotoxicity; G2/M arrest; HDAC INHIBITORS; PHASE-I; ACID; PERSPECTIVES; DERIVATIVES; DISORDERS; CELLS;

D O I：

10.1016/j.bmcl.2016.08.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Amindoximes are geometric isomers of N-hydroxyamidines which are bioisosteres of hydroxamates. Since amindoxime group is capable of chelating transition metal ions including zinc ion, amindoximes should possess histone deacetylases (HDACs) inhibitory activity. In this work, we designed and synthesized a series of amindoximes, examined their inhibitory activities against HDACs, and investigated their cytotoxicity to human cancer cells. Preliminary results demonstrated that amindoximes possessed submicromolar HDACs inhibitory activity, with noteworthy enhancement compared with hydroxamates. Furthermore, the amindoximes arrested HCT116 and A549 cells in G2/M phase and showed good efficacy in inducing cells death. We provided a proof-of-concept that amindoximes could be used as HDACs inhibitors and hold great promise as epigenetic drugs. (C) 2016 Elsevier Ltd. All rights reserved.

引用

页码：4679 / 4683

页数：5

共 32 条

[1] Epigenetic protein families: a new frontier for drug discovery [J].

Arrowsmith, Cheryl H. ;

Bountra, Chas ;

Fish, Paul V. ;

Lee, Kevin ;

Schapira, Matthieu .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (05) :384-400

[2] Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy [J].

Borah, A. ;

Raveendran, S. ;

Rochani, A. ;

Maekawa, T. ;

Kumar, D. S. .

ONCOGENESIS, 2015, 4 :e177-e177

[3] Histone deacetylase inhibitors: Overview and perspectives [J].

Dokmanovic, Milos ;

Clarke, Cathy ;

Marks, Paul A. .

MOLECULAR CANCER RESEARCH, 2007, 5 (10) :981-989

[4] Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders [J].

Falkenberg, Katrina J. ;

Johnstone, Ricky W. .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (09) :673-691

[5] Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors [J].

Finnin M.S. ;

Donigian J.R. ;

Cohen A. ;

Richon V.M. ;

Rifkind R.A. ;

Marks P.A. ;

Breslow R. ;

Pavletich N.P. .

Nature, 1999, 401 (6749) :188-193

[6]

Giannini G, 2012, FUTURE MED CHEM, V4, P1439, DOI [10.4155/FMC.12.80, 10.4155/fmc.12.80]

[7] Design, synthesis and preliminary bioactivity studies of 1,3,4-thiadiazole hydroxamic acid derivatives as novel histone deacetylase inhibitors [J].

Guan, Peng ;

Sun, Feng'e ;

Hou, Xuben ;

Wang, Feng ;

Yi, Fan ;

Xu, Wenfang ;

Fang, Hao .

BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (12) :3865-3872

[8] Low Molecular Weight Amidoximes that Act as Potent Inhibitors of Lysine-Specific Demethylase 1 [J].

Hazeldine, Stuart ;

Pachaiyappan, Boobalan ;

Steinbergs, Nora ;

Nowotarski, Shannon ;

Hanson, Allison S. ;

Casero, Robert A., Jr. ;

Woster, Patrick M. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (17) :7378-7391

[9] Design, synthesis and preliminary biological evaluation of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives as novel histone deacetylase inhibitors [J].

Jiao, Jie ;

Fang, Hao ;

Wang, Xuejian ;

Guan, Peng ;

Yuan, Yumei ;

Xu, Wenfang .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2009, 44 (11) :4470-4476

[10] Design, synthesis, and preliminary biological evaluation of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine derivatives [J].

Jiao, PF ;

Zhao, BX ;

Wang, WW ;

Shin, DS ;

He, QX ;

Wan, MS ;

Shin, DS ;

Miao, JY .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (11) :2862-2867

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