2. Academic Validation
  3. Design, synthesis and biological evaluation of thienopyrimidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors

Design, synthesis and biological evaluation of thienopyrimidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors

  • Eur J Med Chem. 2017 Mar 10:128:293-299. doi: 10.1016/j.ejmech.2017.01.035.
Jiang Wang 1,  Mingbo Su 1,  Tingting Li 1,  Anhui Gao 1,  Wei Yang 1,  Li Sheng 1,  Yi Zang 1,  Jia Li 2,  Hong Liu 3
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China.
  • 2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Electronic address: jli@simm.ac.cn.
  • 3 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, People's Republic of China. Electronic address: hliu@simm.ac.cn.
PMID: 28213282 DOI: 10.1016/j.ejmech.2017.01.035
Abstract

New thienopyrimidine hydroxamic acid derivatives as HDACs inhibitors were designed, synthesized and evaluated. All compounds were evaluated for their ability to inhibit recombinant human HDAC1, HDAC3, and HDAC6 isoforms and in vitro anti-proliferative activity on tumor cell lines RMPI 8226 and HCT 116. Most of these compounds displayed good to excellent inhibitory activities against HDACs. The IC50 values of compound 9m against HDAC1, HDAC3, and HDAC6 was 29.81 ± 0.52 nM, 24.71 ± 1.16 nM, and 21.29 ± 0.32 nM. Most of these compounds showed strong anti-proliferative activity against human Cancer cell lines including RMPI 8226 and HCT 116. The IC50 values of compound 9m against RPMI 8226 and HCT 116 proliferation were 0.97 ± 0.072 μM and 1.01 ± 0.033 μM, respectively. In addition, compound 9m noticeably up-regulated the level of histone H3 acetylation at the low concentration of 0.3 μM.

Keywords

Anti-proliferation; HDAC inhibitor; Structure-activity relationship; Thienopyrimidine; Western blot.

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