title: Structural modifications of camptothecin and effects on topoisomerase I inhibition.
abstract: Camptothecin (1), a potent antitumor alkaloid, is known to inhibit topoisomerase I, an enzyme that relaxes supercoiled DNA. Modifications have been made to the B, D, and E rings of this natural product. Specifically, compounds 2-10 either have an ester moiety in place of the E ring lactone, a methyl ester attached to position 14, a saturated (or nonexistent) deaza B ring, or contain a combination of these permutations. We have conducted in vitro assays against the topoisomerase I relaxation reaction which verify the necessity for a lactone in the E ring. Furthermore, steric requirements at position 14 are shown to be crucial for activity, and planarity of the A and B rings of camptothecin is also implicated in the ability of the drug to inhibit topoisomerase I. Speculation on the nature of the drug binding pocket is presented.
authors.affiliation: Sterling Laboratory of Chemistry, Yale University, New Haven, Connecticut 06511.
authors.forename: R T
authors.initials: RT
authors.lastname: Crow
authors.forename: D M
authors.initials: DM
authors.lastname: Crothers
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002417:Cattle; D004587:Electrophoresis, Agar Gel; D066298:In Vitro Techniques; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D059004:Topoisomerase I Inhibitors; D002166:Camptothecin