title: Production of 8-demethylgeldanamycin and 4,5-epoxy-8-demethylgeldanamycin from a recombinant strain of Streptomyces hygroscopicus.
abstract: Two new geldanamycin derivatives produced by genetic engineering of Streptomyces hygroscopicus strain K309-27-1 were isolated and characterized. Removal of the 8-methyl group of geldanamycin was achieved by replacing the AT4 domain of the polyketide synthase with a malonyl AT domain. The resulting strain produced 8-demethyl geldanamycin (2) and 4,5-epoxy-8-demethylgeldanamycin (3). The structures of both molecules were elucidated through interpretation of 1D and 2D NMR data as well as comparison with authentic geldanamycin derivatives. Compounds 2 and 3 displayed moderate cytotoxicity against the human breast cancer cell line SK-BR-3.
authors.affiliation: Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545, USA. buchanan@kosan.com
authors.forename: Greg O
authors.initials: GO
authors.lastname: Buchanan
authors.forename: Rika
authors.initials: R
authors.lastname: Regentin
authors.forename: Misty
authors.initials: M
authors.lastname: Piagentini
authors.forename: Andreas
authors.initials: A
authors.lastname: Rascher
authors.forename: Robert
authors.initials: R
authors.lastname: McDaniel
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Galazzo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Licari
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D016227:Benzoquinones; D045744:Cell Line, Tumor; D005818:Genetic Engineering; D006801:Humans; D047029:Lactams, Macrocyclic; D015394:Molecular Structure; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013302:Streptomyces / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C501147:4,5-epoxy-8-demethylgeldanamycin; C501146:8-demethylgeldanamycin; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; C001277:geldanamycin