FLAVONOIDS AS DNA TOPOISOMERASE ANTAGONISTS AND POISONS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Selected flavonoids were tested for their ability to inhibit the catal ytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercet in, fisetin, and morin were found to inhibit both enzymes, while phlor etin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II wi thout inhibiting topo I. Flavonoids demonstrating potent rope I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3' , and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid cope I inhibitory action. A C -2,C-3 double bond was also required, but when the A ring is opened, t he requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage com plex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavag e complex, bur prunetin, quercetin, kaempferol, and apigenin stabilize d the topo II DNA-complex. Competition experiments have shown that gen istein-induced topo II-mediated DNA cleavage can be inhibited by myric etin, suggesting that both types of inhibitors (antagonists and poison s) interact with the same functional domain of their target enzyme. Th ese results are of use for the selection of flavonoids that can inhibi t specific topoisomerases at specific stages of the topoisomerization reaction.