2. Academic Validation
  3. Design, synthesis and biological evaluation of isoquinoline-based derivatives as novel histone deacetylase inhibitors

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

  • Bioorg Med Chem. 2015 Sep 1;23(17):5881-90. doi: 10.1016/j.bmc.2015.06.071.
Wei Yang 1,  Lixuan Li 2,  Yulan Wang 3,  Xiaowei Wu 1,  Tingting Li 1,  Nan Yang 1,  Mingbo Su 3,  Li Sheng 3,  Mingyue Zheng 3,  Yi Zang 3,  Jia Li 4,  Hong Liu 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; East China Normal University, Institutes for Advanced Interdisciplinary Research, North Zhongshan Road Campus: 3663 N. Zhongshan Rd., Shanghai 200062, PR China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; East China Normal University, Institutes for Advanced Interdisciplinary Research, North Zhongshan Road Campus: 3663 N. Zhongshan Rd., Shanghai 200062, PR China. Electronic address: jli@mail.shcnc.ac.cn.
  • 5 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address: hliu@mail.shcnc.ac.cn.
PMID: 26211462 DOI: 10.1016/j.bmc.2015.06.071
Abstract

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 10 c 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 10 a-h against RPMI 8226 Cancer cell proliferation were all below 1 μM. HCT 116 cell was sensitive to the compounds 10 a, 10 f-g and 18 a with the IC50 values <0.3 μM. 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.

Keywords

HDACs; HDACs inhibitor; Hydroxamic acid; Isoquinoline.

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