Document Detail


Design, synthesis, and biological activity of boronic acid-based histone deacetylase inhibitors.
MedLine Citation:
PMID:  19419205     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Guided by the proposed catalytic mechanism of histone deacetylases (HDACs), we designed and synthesized a series of boronic acid-based HDAC inhibitors bearing an alpha-amino acid moiety. In this series, compounds (S)-18, 20, and 21 showed potent HDAC-inhibitory activity, highlighting the significance of the (S)-amino acid moiety. In cancer cell growth inhibition assays, compounds (S)-18, 20, and 21 exerted strong activity, and the values of the ratio of the concentration causing 50% growth inhibition (GI(50)) to the concentration causing 50% enzyme inhibition (IC(50)), i.e., GI(50)/IC(50), were low. The potency of these compounds was similar to that of clinically used suberoylanilide hydroxamic acid (SAHA) (2). The results of Western blot analysis indicated that the cancer cell growth-inhibitory activity of compounds (S)-18, 20, and 21 is the result of HDAC inhibition. A molecular modeling study suggested that the hydrated boronic acid interacts with zinc ion, Tyr residue, and His residue in the active site of HDACs. Our findings indicate that these boronic acid derivatives represent an entry into a new class of HDAC inhibitors.
Authors:
Nobuaki Suzuki; Takayoshi Suzuki; Yosuke Ota; Tatsuya Nakano; Masaaki Kurihara; Haruhiro Okuda; Takao Yamori; Hiroki Tsumoto; Hidehiko Nakagawa; Naoki Miyata
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-07     Completed Date:  2009-06-02     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2909-22     Citation Subset:  IM    
Affiliation:
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biocatalysis
Boronic Acids / chemical synthesis,  chemistry*,  pharmacology*
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology*
Histone Deacetylase Inhibitors*
Histone Deacetylases / chemistry,  metabolism
Humans
Inhibitory Concentration 50
Models, Molecular
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; EC 3.5.1.98/Histone Deacetylases

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