title: (7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ieda
authors.affiliation: Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Sota
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. Electronic address: deco@phar.nagoya-cu.ac.jp.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology*; D004951:Esterification; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D055668:Photochemical Processes; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
keywords: Caged compounds; Epigenetics; HDAC inhibitors; Histone deacetylases (HDACs); Photolabile protecting group