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

Yingjie Zhang; Jinhong Feng; Chunxi Liu; Lei Zhang; Jie Jiao; Hao Fang; Li Su; Xiaopan Zhang; Jian Zhang; Minyong Li; Binghe Wang; Wenfang Xu

doi:10.1016/j.bmc.2010.01.060

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

Bioorg Med Chem. 2010 Mar 1;18(5):1761-72. doi: 10.1016/j.bmc.2010.01.060. Epub 2010 Feb 6.

Authors

Yingjie Zhang¹, Jinhong Feng, Chunxi Liu, Lei Zhang, Jie Jiao, Hao Fang, Li Su, Xiaopan Zhang, Jian Zhang, Minyong Li, Binghe Wang, Wenfang Xu

Affiliation

¹ Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, PR China.

PMID: 20171895
DOI: 10.1016/j.bmc.2010.01.060

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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