Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships.
Selected flavonoids were tested for their ability to inhibit the
catalytic activity of DNA topoisomerase (topo) I and II. Myricetin,
quercetin, fisetin, and morin were found to inhibit both enzymes, while
phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo
II without inhibiting topo I. Flavonoids demonstrating potent topo 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 topo I inhibitory
action. A C-2, C-3 double bond was also required, but when the A ring
is opened, the requirement for the double bond was eliminated.
Genistein has been previously reported to stabilize the covalent topo
II-DNA cleavage complex 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 cleavage complex, but prunetin, quercetin,
kaempferol, and apigenin stabilized the topo II DNA-complex.
Competition experiments have shown that genistein-induced topo
II-mediated DNA cleavage can be inhibited by myricetin, suggesting that
both types of inhibitors (antagonists and poisons) interact with the
same functional domain of their target enzyme. These results are of use
for the selection of flavonoids that can inhibit specific
topoisomerases at specific stages of the topoisomerization reaction.
Selected flavonoids were tested for their ability to inhibit the
catalytic activity of DNA topoisomerase (topo) I and II. Myricetin,
quercetin, fisetin, and morin were found to inhibit both enzymes, while
phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo
II without inhibiting topo I. Flavonoids demonstrating potent topo 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 topo I inhibitory
action. A C-2, C-3 double bond was also required, but when the A ring
is opened, the requirement for the double bond was eliminated.
Genistein has been previously reported to stabilize the covalent topo
II-DNA cleavage complex 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 cleavage complex, but prunetin, quercetin,
kaempferol, and apigenin stabilized the topo II DNA-complex.
Competition experiments have shown that genistein-induced topo
II-mediated DNA cleavage can be inhibited by myricetin, suggesting that
both types of inhibitors (antagonists and poisons) interact with the
same functional domain of their target enzyme. These results are of use
for the selection of flavonoids that can inhibit specific
topoisomerases at specific stages of the topoisomerization reaction.