Synthesis and evaluation of novel analogues of ripostatins

Wufeng Tang, Shuang Liu, David Degen, Richard H. Ebright, Evgeny V. Prusov

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12310-12319
Number of pages10
JournalChemistry - A European Journal
Volume20
Issue number38
DOIs
StatePublished - Sep 15 2014

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

Keywords

  • antibacterial agents
  • antibiotics
  • natural products
  • polymerase inhibitors
  • structure-activity relationships

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