Novel histone deacetylase inhibitors: Design, synthesis, enzyme inhibition, and binding mode study of SAHA-based non-hydroxamates

In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed and synthesized as (i). substrate (acetyl lysine) analogues (compounds 3-7), (ii). analogues bearing various functional groups expect...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-12, Vol.13 (24), p.4321-4326
Main Authors: SUZUKI, Takayoshi, NAGANO, Yuki, MATSUURA, Azusa, KOHARA, Arihiro, NINOMIYA, Shin-Ichi, KOHDA, Kohfuku, MIYATA, Naoki
Format: Article
Language:English
Subjects:
Antineoplastic agents
Binding Sites
Biological and medical sciences
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General aspects
Histone Deacetylase Inhibitors
Histone Deacetylases - chemistry
Hydroxamic Acids - chemical synthesis
Hydroxamic Acids - chemistry
Hydroxamic Acids - pharmacology
Indicators and Reagents
Lysine
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Protein Conformation
Structure-Activity Relationship
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Description
Summary:In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) were designed and synthesized as (i). substrate (acetyl lysine) analogues (compounds 3-7), (ii). analogues bearing various functional groups expected to chelate zinc ion (compounds 8-15), and (iii). analogues bearing nucleophilic functional groups which could bind covalently to HDACs (compounds 16-18). In this series, semicarbazide 8b and bromoacetamides 18b,c were found to be potent HDAC inhibitors for non-hydroxamates.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2003.09.048