(7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity

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• 作者：Naoya Ieda^a ; Sota Yamada^b ; Mitsuyasu Kawaguchi^a ; Naoki Miyata^a ; Hidehiko Nakagawa^a ; ^{deco@phar.nagoya-cu.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Epigenetics ; Histone deacetylases (HDACs) ; HDAC inhibitors ; Photolabile protecting group ; Caged compounds
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：24
• 期：12
• 页码：2789-2793
• 全文大小：911 K

文摘

Histone deacetylases (HDACs) are involved in epigenetic control of the expression of various genes by catalyzing deacetylation of ε-acetylated lysine residues. Here, we report the design, synthesis and evaluation of the (7-diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid (AC-SAHA) as a caged HDAC inhibitor, which releases the known pan-HDAC inhibitor SAHA upon cleavage of the photolabile (7-diethylaminocoumarin-4-yl)methyl protecting group in response to photoirradiation. A key advantage of AC-SAHA is that the caged derivative itself shows essentially no HDAC-inhibitory activity. Upon photoirradiation, AC-SAHA decomposes to SAHA and a 7-diethylaminocoumarin derivative, together with some minor products. We confirmed that AC-SAHA inhibits HDAC in response to photoirradiation in vitro by means of chemiluminescence assay. AC-SAHA also showed photoinduced inhibition of proliferation of human colon cancer cell line HCT116, as determined by MTT assay. Thus, AC-SAHA should be a useful tool for spatiotemporally controlled inhibition of HDAC activity, as well as a candidate chemotherapeutic reagent for human colon cancer.