Design, synthesis, structure--selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors.
To uncover novel histone deacetylase 6 (HDAC6)-selective inhibitors and to elucidate the structural requirements for their inhibitory activity, we designed and prepared a series of thiolate analogues based on the structure of an HDAC6-selective substrate and evaluated their properties by Western blotting and enzyme assays. Several thiolate analogues were found to be potent and selective HDAC6 inhibitors. Study of the structure-selectivity relationship revealed that the presence of a bulky alkyl group and tert-butylcarbamate group in these compounds is important for HDAC6-selective inhibition. Compounds 16b and 20b, the most selective and active compounds in this series, exerted a synergistic inhibition of cancer cell growth in combination with paclitaxel. They also blocked the growth of estrogen receptor alpha-positive breast cancer MCF-7 cells that had been treated with estrogen. These findings suggested that HDAC6-selective inhibitors have potential as anticancer agents.
Itoh
Yukihiro
Y
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Suzuki
Takayoshi
T
Kouketsu
Akiyasu
A
Suzuki
Nobuaki
N
Maeda
Satoko
S
Yoshida
Minoru
M
Nakagawa
Hidehiko
H
Miyata
Naoki
N
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; C524709:S-6-(tert-butoxycarbonyl)-7-(cyclopentylamino)-7-oxoheptyl 2-methylpropanethioate; C524710:S-7-(adamant-1-ylamino)-6-(tert-butoxycarbonyl)-7-oxoheptyl 2-methylpropanethioate; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel