Flavonoids as DNA topoisomerase antagonists and poisons: Structure-activity relationships

Andreas Constantinou, Rajendra Mehta, Constance Runyan, Kandala Rao, Andrew T M Vaughan, Richard Moon

Research output: Contribution to journalArticle

240 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalJournal of Natural Products
Volume58
Issue number2
StatePublished - 1995
Externally publishedYes

Fingerprint

DNA topoisomerase
DNA topoisomerase (ATP-hydrolysing)
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Poisons
structure-activity relationships
Structure-Activity Relationship
Flavonoids
antagonists
flavonoids
DNA Cleavage
myricetin
Genistein
Quercetin
genistein
kaempferol
quercetin
Phloretin
Catalytic DNA
Apigenin

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Flavonoids as DNA topoisomerase antagonists and poisons : Structure-activity relationships. / Constantinou, Andreas; Mehta, Rajendra; Runyan, Constance; Rao, Kandala; Vaughan, Andrew T M; Moon, Richard.

In: Journal of Natural Products, Vol. 58, No. 2, 1995, p. 217-225.

Research output: Contribution to journalArticle

Constantinou, A, Mehta, R, Runyan, C, Rao, K, Vaughan, ATM & Moon, R 1995, 'Flavonoids as DNA topoisomerase antagonists and poisons: Structure-activity relationships', Journal of Natural Products, vol. 58, no. 2, pp. 217-225.
Constantinou, Andreas ; Mehta, Rajendra ; Runyan, Constance ; Rao, Kandala ; Vaughan, Andrew T M ; Moon, Richard. / Flavonoids as DNA topoisomerase antagonists and poisons : Structure-activity relationships. In: Journal of Natural Products. 1995 ; Vol. 58, No. 2. pp. 217-225.
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