Design, synthesis and preliminary activity assay of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as novel Histone deacetylases (HDACs) inhibitors.

Abstract

Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC(50)=0.58+/-0.10 microM), 7d (IC(50)=1.00+/-0.16 microM), 8l (IC(50)=1.06+/-0.14 microM), 7i (IC(50)=1.17+/-0.19 microM) and 7a (IC(50)=1.29+/-0.15 microM) possessed better HDACs inhibitory activity than Vorinostat (IC(50)=1.48+/-0.20 microM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure-activity relationships are also briefly discussed.

• Authors: Yingjie Zhang, Jinhong Feng, Chunxi Liu, Lei Zhang, Jie Jiao, Hao Fang, Li Su, Xiaopan Zhang, Jian Zhang, Minyong Li, Binghe Wang, Wenfang Xu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 5 Pg. 1761-72 (Mar 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20171895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Isoquinolines
• Tetrahydroisoquinolines
• benzyl 7-(2-(hydroxyamino)-2-oxoethoxy)-3-(phenethylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
• tert-butyl 7-(2-(hydroxyamino)-2-oxoethoxy)-3-(4-methoxyphenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate
• 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
• Histone Deacetylases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Catalytic Domain
• Cell Line, Tumor
• Computer Simulation
• Drug Design
• Drug Screening Assays, Antitumor
• HL-60 Cells
• Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Hydroxamic Acids (chemical synthesis, chemistry, pharmacology)
• Isoquinolines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tetrahydroisoquinolines (chemical synthesis, chemistry, pharmacology)