Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors

被引:16
|
作者
Yang, Wei [1 ]
Li, Lixuan [2 ,3 ]
Wang, Yulan [2 ]
Wu, Xiaowei [1 ]
Li, Tingting
Yang, Nan
Su, Mingbo [2 ]
Sheng, Li [2 ]
Zheng, Mingyue [2 ]
Zang, Yi [2 ]
Li, Jia [2 ,3 ]
Liu, Hong [1 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
[3] E China Normal Univ, Inst Adv Interdisciplinary Res, Shanghai 200062, Peoples R China
基金
中国国家自然科学基金;
关键词
HDACs; HDACs inhibitor; Hydroxamic acid; Isoquinoline; HDAC INHIBITORS; CANCER; SAHA; DEPSIPEPTIDE; ACETYLATION;
D O I
10.1016/j.bmc.2015.06.071
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The design, synthesis and biological evaluation of a series of isoquinoline-based hydroxamic acid compounds as novel HDACs inhibitors were reported herein. A detailed SAR study showed most of the compounds displayed good to excellent inhibitory activities against HDAC1, 3, 6. The IC50 values of compound 10c against HDAC1, 3, 6 were 4.17 +/- 0.11 nM, 4.00 +/- 0.10 nM, 3.77 +/- 0.07 nM, respectively. Most of the compounds showed great anti-proliferative activities against RPMI 8226, HCT 116 and Hep G2 cells. The IC50 values of compounds 10a-h against RPMI 8226 cancer cell proliferation were all below 1 mu M. HCT 116 cell was sensitive to the compounds 10a, 10f-g and 18a with the IC50 values <0.3 mu M. The active compounds 10a-d did not show inhibitory activity against hERG channel. All these evidence indicated these compounds had great potential as HDACs inhibitors for the further development. (C) 2015 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5881 / 5890
页数:10
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