title: Tyrosyl-DNA phosphodiesterase 1 inhibitor from an anamorphic fungus.
abstract: Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that catalyzes hydrolysis of 3'-phosphotyrosyl bonds and is involved in repair of irreversible topoisomerase I (Top1)-DNA covalent complexes. Tdp1 inhibitors are regarded as potential cancer therapeutics in combination with Top1 inhibitors, which are currently used to treat human cancers. While screening for Tdp1 inhibitors, we discovered a novel compound, JBIR-21 (1), from the culture of an anamorphic fungus, RF-13305. The structure of 1 was established by extensive NMR and MS analyses. Compound 1 showed inhibitory activity against Tdp1 (IC(50) value, 18 μM) and cytotoxic activity against cancer cell lines (IC(50) values, 3.5-13 μM). Compound 1 also exhibited antitumor activity in a mouse xenograft model without adverse effects.
authors.affiliation: Biomedicinal Information Research Center (BIRC), Japan Biological Informatics Consortium (JBIC), 2-4-7 Aomi, Tokyo 135-0064, Japan. motoki-takagi@aist.go.jp
authors.forename: Motoki
authors.initials: M
authors.lastname: Takagi
authors.forename: Jun-ya
authors.initials: JY
authors.lastname: Ueda
authors.forename: Ji-Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Junko
authors.initials: J
authors.lastname: Hashimoto
authors.forename: Miho
authors.initials: M
authors.lastname: Izumikawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Murakami
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
mesh_terms: D000818:Animals; D004354:Drug Screening Assays, Antitumor; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: C573368:JBIR-21; D012717:Sesquiterpenes; D010727:Phosphoric Diester Hydrolases; C498508:TDP1 protein, human