title: Production of anticancer polyenes through precursor-directed biosynthesis.
abstract: The biosynthesis of the pyrrolyl moiety of the fungal metabolite rumbrin originates from pyrrole-2-carboxylic acid. In an effort to produce novel derivatives with enhanced biological activity a series of substituted pyrrole-2-carboxylates were synthesised and incubated with the producing organism, Auxarthron umbrinum. Several 4-halo-pyrrole-2-carboxylic acids were incorporated into the metabolite yielding three new derivatives: 3-fluoro-, 3-chloro- and 3-bromo-isorumbrin, which were generated in milligram quantities enabling cytotoxicity assays to be conducted. The 3-chloro- and 3-bromo-isorumbrins had improved activity against HeLa cells compared with rumbrin; 3-bromoisorumbrin also showed dramatically improved activity towards a lung cancer cell line (A549).
authors.affiliation: School of Biomolecular and Biomedical Sciences, Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Republic of Ireland.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Clark
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Connor
authors.forename: Deirdre
authors.initials: D
authors.lastname: Fox
authors.forename: Jacques
authors.initials: J
authors.lastname: Leroy
authors.forename: Cormac D
authors.initials: CD
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D005658:Fungi / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000188:drug therapy; D011090:Polyenes / Q000737:chemistry* / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011090:Polyenes; D011753:Pyrones; D011758:Pyrroles; C082417:rumbrin; C002986:2-pyrrolecarboxylic acid; D011392:Proline