A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase i

Sidney M. Hecht, David E. Berry, Laurie J. Mackenzie, Robert W. Busby, Christopher A. Nasuti

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

While the design of molecules that inhibit or antagonize the functions of specific macromolecules is now well precedented, in many cases the structural information requisite to the design process is lacking. The tools of molecular biology can now furnish the target macromolecules for use in mechanism-based exploration; highly defined assays can be devised based upon the known biochemistry of these macromolecules to permit the discovery of novel inhibitors or antagonists present in chemical collections. Presently, we describe a set of assays directed toward the discovery of novel inhibitors of eukaryotic topoisomerase I, an enzyme critical to maintenance of chromosomal DNA topology and therefore essential for normal replication and transcription. The identification of chebulagic acid as an extraordinarily potent and mechanistically novel inhibitor of topoisomerase I illustrates the potential of this approach.

Original languageEnglish (US)
Pages (from-to)401-413
Number of pages13
JournalJournal of Natural Products
Volume55
Issue number4
DOIs
StatePublished - Apr 1 1992
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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