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

Takayoshi Suzuki; Yuki Nagano; Azusa Matsuura; Arihiro Kohara; Shin-ichi Ninomiya; Kohfuku Kohda; Naoki Miyata

doi:10.1016/j.bmcl.2003.09.048

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

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4321-6. doi: 10.1016/j.bmcl.2003.09.048.

Authors

Takayoshi Suzuki¹, Yuki Nagano, Azusa Matsuura, Arihiro Kohara, Shin-ichi Ninomiya, Kohfuku Kohda, Naoki Miyata

Affiliation

¹ Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.

PMID: 14643318
DOI: 10.1016/j.bmcl.2003.09.048

Abstract

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.

Publication types

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

MeSH terms

Binding Sites
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Deacetylase Inhibitors*
Histone Deacetylases / chemistry
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Indicators and Reagents
Lysine
Models, Molecular
Molecular Conformation
Protein Conformation
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Histone Deacetylase Inhibitors
Hydroxamic Acids
Indicators and Reagents
Histone Deacetylases
Lysine