Synthesis and in Vitro and in Vivo Biological Evaluation of Tissue-Specific Bisthiazole Histone Deacetylase (HDAC) Inhibitors

  • J Med Chem. 2020 Jan 23;63(2):804-815. doi: 10.1021/acs.jmedchem.9b01792.
Shu-Wei Zhang  1  2 ,  Chao-Jun Gong  1 ,  Ming-Bo Su  1 ,  Fei Chen  1 ,  Ting He  3 ,  Yang-Ming Zhang  1  4 ,  Qian-Qian Shen  3 ,  Yi Su  3 ,  Jian Ding  3 ,  Jia Li  1 ,  Yi Chen  3 ,  Fa-Jun Nan  1  4
Affiliations
  • 1. State Key Laboratory of Drug Research, the National Center for Drug Screening , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , 201203 , China.
  • 2. University of Chinese Academy of Sciences , No. 19A Yuquan Road , Beijing 100049 , P. R. China.
  • 3. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • 4. Yantai Key Laboratory of Nanomedicine & Advanced Preparations , Yantai Institute of Materia Medica , Shandong 264000 , China.
PMID: 31855601 DOI: 10.1021/acs.jmedchem.9b01792
Abstract

A series of bisthiazole-based hydroxamic acids as novel potent HDAC inhibitors was developed during our previous work. In the present work, a new series of highly potent bisthiazole-based compounds were designed and synthesized. Among the prepared compounds, compound H13, which contains an α-(S)-methyl-substituted benzyl group, displays potent inhibitory activity toward human HDACs and several Cancer cells lines. Compound H13 has a favorable PK profile and high tissue distribution specificity in the colon, as well as good efficacy in the AOM-DSS mouse model for colitis-associated colonic tumorigenesis.