Comparative analysis of topoisomerase IB inhibition and DNA intercalation by flavonoids and similar compounds: structural determinates of activity.
Flavonoids and other polyphenolic compounds have been shown to inhibit human topoisomerase IB (topo I) through both inhibition of relaxation activity and through stabilization of the cleavable complex (poisoning). Some flavonoids have also been shown to intercalate DNA, and an association of topoisomerase inhibition with intercalation has been noted. We surveyed 34 polyphenolic compounds, primarily flavonoid glycones and aglycones, for their ability to inhibit topo I and to intercalate DNA using an in vitro gel electrophoresis method. We show that the most potent topo I poisons are the flavones and flavonols, and that these generally, but not always, are found to be DNA intercalators. There was no clear correlation, however, of topo-I-poisoning activity with the degree of DNA unwinding. Surprisingly, both DNA intercalation and topo I poisoning were shown to occur with some flavone glycones, including the C-glycosylflavone orientin. Inhibition of relaxation activity by flavonoids was found to be difficult to quantify and was most likely to be due to non-specific inhibition through flavonoid aggregation. As part of a structure-activity analysis, we also investigated the acid-base chemistry of flavonoids and determined that many flavonoids show acid-base activity with a pK(a) in the physiological pH region. For this reason, subtle pH changes can have significant effects on solution activity of flavonoids and their concomitant biological activity. In addition, these effects may be complicated by pH-dependent aggregation and oxidative degradation. Finally, we develop a simple model for the intercalation of flavonoids into DNA and discuss possible consequences of intercalation and topoisomerase inhibition on a number of cellular processes.
Webb
Michael R
MR
Department of Viticulture and Enology, University of California-Davis, 1 Shields Avenue, Davis, CA 95616, USA.
Ebeler
Susan E
SE
D000818:Animals; D002417:Cattle; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D047311:Luteolin / Q000378:metabolism / Q000494:pharmacology; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D059808:Polyphenols; D011794:Quercetin / Q000378:metabolism / Q000494:pharmacology; D012710:Serum Albumin, Bovine; D012965:Sodium Chloride / Q000494:pharmacology; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007364:Intercalating Agents; D010636:Phenols; D059808:Polyphenols; D012996:Solutions; D059004:Topoisomerase I Inhibitors; D012710:Serum Albumin, Bovine; D012965:Sodium Chloride; D004247:DNA; D011794:Quercetin; D004264:DNA Topoisomerases, Type I; D047311:Luteolin