Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates.
To find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, a series of compounds modeled after suberoylanilide hydroxamic acid (SAHA) was designed and synthesized. In this series, compound 7, in which the hydroxamic acid of SAHA is replaced by a thiol, was found to be as potent as SAHA, and optimization of this series led to the identification of HDAC inhibitors more potent than SAHA. In cancer cell growth inhibition assay, S-isobutyryl derivative 51 showed strong activity, and its potency was comparable to that of SAHA. The cancer cell growth inhibitory activity was verified to be the result of histone hyperacetylation and subsequent induction of p21(WAF1/CIP1) by Western blot analysis. Kinetical enzyme assay and molecular modeling suggest the thiol formed by enzymatic hydrolysis within the cell interacts with the zinc ion in the active site of HDACs.
Suzuki
Takayoshi
T
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. suzuki@phar.nagoya-cu.ac.jp
Nagano
Yuki
Y
Kouketsu
Akiyasu
A
Matsuura
Azusa
A
Maruyama
Sakiko
S
Kurotaki
Mineko
M
Nakagawa
Hidehiko
H
Miyata
Naoki
N
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077337:Vorinostat
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D013844:Thiazoles; C498566:thioisobutyric acid S-(6-(4-phenyl-2-thiazolylcarbamoyl)hexyl) ester; D000077337:Vorinostat; D006655:Histone Deacetylases