title: 14-azacamptothecin: a potent water-soluble topoisomerase I poison.
abstract: On the basis of an analysis of luotonin A and its D-ring deaza analogue as topoisomerase I poisons and topoisomerase I-dependent cytotoxic agents, a novel analogue of the structurally related antitumor antibiotic camptothecin (CPT) was prepared. 14-Azacamptothecin was found to have much greater aqueous solubility than CPT, to inhibit topoisomerase I-mediated DNA relaxation more efficiently than CPT, and to stabilize the covalent binary complex to almost the same extent. 14-Aza CPT was found to be slightly less active than CPT in mediating cytotoxicity toward yeast expressing human topoisomerase I, possibly as a consequence of its greater off-rate from the CPT-topoisomerase I-DNA ternary complex.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA.
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Rahier
authors.forename: Brian M
authors.initials: BM
authors.lastname: Eisenhauer
authors.forename: Rong
authors.initials: R
authors.lastname: Gao
authors.forename: S J
authors.initials: SJ
authors.lastname: Thomas
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D059004:Topoisomerase I Inhibitors; D014867:Water / Q000737:chemistry
chemical_list: C499708:14-azacamptothecin; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011809:Quinones; D059004:Topoisomerase I Inhibitors; C480761:luotonin A; D014867:Water; D002166:Camptothecin