ABSTRACT
Structure-activity studies were employed to investigate the stabilization of DNA-topoisomerases I and II covalent binary complexes by topopyrone analogues. The synthesis of five new topopyrone derivatives and study of their ability to stabilize DNA-topoisomerase I and DNA-topoisomerase II covalent binary complexes are described. The biochemical assays suggest that the orientation of the fused 1,4-pyrone ring and halogen substituents contribute importantly to the overall potency of the topopyrones as topoisomerase poisons.
Subject(s)
DNA Topoisomerases, Type II/metabolism , DNA Topoisomerases, Type I/metabolism , Pyrones/chemical synthesis , Pyrones/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Anthraquinones/chemistry , Humans , Molecular Structure , Pyrones/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topoisomerase II Inhibitors/chemistryABSTRACT
Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities. Also measured were the abilities of several of the analogues to inhibit respiration as judged by a shift to glycolysis, and to inhibit the growth of several mammalian cell lines. The nature of the pyrone ring was shown to be important to potency of inhibition, as was the length and nature of substituents in the side chain of the analogues.
