Inhibition of topoisomerase I function by coralyne and 5,6-dihydrocoralyne.
The antitumor agent coralyne and a number of structural analogues were found to be inhibitors of DNA topoisomerase I and were characterized biochemically. Several of these analogues stabilized the covalent binary complex formed between calf thymus topoisomerase I and pSP64 plasmid DNA; coralyne and 5,6-dihydrocoralyne had the greatest potency as inhibitors in this assay. In common with camptothecin, the effects of coralyne and 5,6-dihydrocoralyne were reversed in the presence of increasing salt concentration or temperature, consistent with the interpretation that both functioned mechanistically in a fashion analogous to camptothecin. The sequence specificity of DNA cleavage by coralyne and 5,6-dihydrocoralyne was also studied in comparison with camptothecin using a 471-bp DNA duplex as a substrate for topoisomerase I. Seven sites of cleavage were apparent, four of which were shared in common by coralyne, 5,6-dihydrocoralyne and camptothecin. Coralyne and 5,6-dihydrocoralyne produced cleavage at one sequence, 5'-TCTC decreases GTAA=3', that was not apparent in the presence of camptothecin; correspondingly, two cleavage bands appeared only when camptothecin was present. Coralyne and 5,6-dihydrocoralyne also inhibited topoisomerase I-mediated relaxation of supercoiled plasmid DNA. Coralyne was the most potent inhibitor of DNA relaxation; the effects of camptothecin and 5,6-dihydrocoralyne were roughly equal. At high concentrations, coralyne completely suppressed the formation of the topoisomerase I-DNA covalent binary complex.
Wang
L K
LK
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Rogers
B D
BD
Hecht
S M
SM
D001483:Base Sequence; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000494:pharmacology; D004355:Drug Stability; D008969:Molecular Sequence Data; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D001600:Berberine Alkaloids; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C000666:coralyne; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II