title: Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP.
abstract: Natural products have been utilized for drug discovery. To increase the source diversity, we generated a new chemical library consisting of chemically modified microbial metabolites termed 'Unnatural Natural Products' by chemical conversion of microbial metabolites in crude broth extracts followed by purification of reaction products with the LC-photo diode array-MS system. Using this library, we discovered an XIAP inhibitor, C38OX6, which restored XIAP-suppressed enzymatic activity of caspase-3 in vitro. Furthermore, C38OX6 sensitized cancer cells to anticancer drugs, whereas the unconverted natural product did not. These findings suggest that our library could be a useful source for drug seeds.
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kawamura
authors.forename: Kohei
authors.initials: K
authors.lastname: Matsubara
authors.forename: Hitomi
authors.initials: H
authors.lastname: Otaka
authors.forename: Etsu
authors.initials: E
authors.lastname: Tashiro
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shindo
authors.forename: Ryo C
authors.initials: RC
authors.lastname: Yanagita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Masaya
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008235:Lyngbya Toxins / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; C568689:C38OX6 compound; D061945:Caspase Inhibitors; D007094:Imides; D026121:Indole Alkaloids; D008235:Lyngbya Toxins; D054852:Small Molecule Libraries; D051636:X-Linked Inhibitor of Apoptosis Protein; C022176:teleocidins; D053148:Caspase 3