title: A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I.
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 mechanically novel inhibitor of topoisomerase I illustrates the potential of this approach.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville 22901.
authors.forename: S M
authors.initials: SM
authors.lastname: Hecht
authors.forename: D E
authors.initials: DE
authors.lastname: Berry
authors.forename: L J
authors.initials: LJ
authors.lastname: MacKenzie
authors.forename: R W
authors.initials: RW
authors.lastname: Busby
authors.forename: C A
authors.initials: CA
authors.lastname: Nasuti
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004587:Electrophoresis, Agar Gel; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology*; D047348:Hydrolyzable Tannins; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D010936:Plant Extracts / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors
chemical_list: D001578:Benzopyrans; D004278:DNA, Superhelical; D005960:Glucosides; D047348:Hydrolyzable Tannins; D010936:Plant Extracts; D059004:Topoisomerase I Inhibitors; C076178:chebulagic acid; C049096:corilagin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin