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 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.
Suzuki
Takayoshi
T
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Nagano
Yuki
Y
Matsuura
Azusa
A
Kohara
Arihiro
A
Ninomiya
Shin-ichi
S
Kohda
Kohfuku
K
Miyata
Naoki
N
D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007202:Indicators and Reagents; D008239:Lysine; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D006655:Histone Deacetylases; D008239:Lysine