title: Synthesis and evaluation of novel analogues of ripostatins.
abstract: Ripostatins are polyene macrolactones isolated from the myxobacterium Sorangium cellulosum. They exhibit antibiotic activity by inhibiting bacterial RNA polymerase (RNAP) through a binding site and mechanism that are different from those of current antibacterial drugs. Thus, the ripostatins serve as starting points for the development of new anti-infective agents with a novel mode of action. In this work, several derivatives of ripostatins were produced. 15-Desoxyripostatin A was synthesized by using a one-pot carboalumination/cross-coupling. 5,6-Dihydroripostatin A was constructed by utilizing an intramolecular Suzuki cross-coupling macrolactonization approach. 14,14'-Difluororipostatin A and both epimeric 14,14'-difluororipostatins B were synthesized by using a Reformatsky type aldol addition of a haloketone, Stille cross-coupling, and ring-closing metathesis. The RNAP-inhibitory and antibacterial activities are presented. Structure-activity relationships indicate that the monocyclic keto-ol form of ripostatin A is the active form of ripostatin A, that the ripostatin C5-C6 unsaturation is important for activity, and that C14 geminal difluorination of ripostatin B results in no loss of activity.
authors.affiliation: Helmholtz-Zentrum für Infektionsforschung (HZI), Inhoffenstrasse 7, 38124 Braunschweig (Germany), Fax: (+49) 0531-6181-9499.
authors.forename: Wufeng
authors.initials: W
authors.lastname: Tang
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Degen
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ebright
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Prusov
mesh_terms: D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007783:Lactones; C096601:ripostatin B
keywords: antibacterial agents; antibiotics; natural products; polymerase inhibitors; structure-activity relationships
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