title: Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I.
abstract: Topoisomerases are involved in many aspects of DNA metabolism such as replication and transcription reactions. Camptothecins, which stabilize the covalent intermediate of topoisomerase I and DNA are effective, though toxic, drugs for cancer therapy. In this study, a new class of topoisomerase I inhibitors was identified, and their mode of action was characterized using recombinant human topoisomerase I preparations and human HL-60 leukemic cells. Quercetin and the related natural flavones, acacetin, apigenin, kaempferol, and morin, inhibit topoisomerase I-catalyzed DNA religation. In contrast to camptothecin, these compounds do not act directly on the catalytic intermediate and also do not interfere with DNA cleavage. However, formation of a ternary complex with topoisomerase I and DNA during the cleavage reaction inhibits the following DNA religation step. 3,3',4',7-Tetrahydroxy-substituted flavones stabilize the covalent topoisomerase I-DNA intermediate most efficiently. Enhanced formation of covalent topoisomerase I-DNA complexes was also demonstrated in human HL-60 cells. In contrast, synthetic 3,5'-dibromo- 4'-hydroxy-3-methylflavones bind selectively to topoisomerase I in its non-DNA-bound form and block the following DNA binding step. As a consequence, these synthetic flavonoids are capable of counteracting topoisomerase I-directed effects of camptothecin. Inhibition of DNA binding is obtained by voluminous hydrophobic substituents in 6-position of the flavone structure. Our data show that selective inhibitors of both half-reactions of topoisomerase I can be derived from the flavone structure.
authors.affiliation: Medizinische Poliklinik, University of Würzburg, Federal Republic of Germany.
authors.forename: F
authors.initials: F
authors.lastname: Boege
authors.forename: T
authors.initials: T
authors.lastname: Straub
authors.forename: A
authors.initials: A
authors.lastname: Kehr
authors.forename: C
authors.initials: C
authors.lastname: Boesenberg
authors.forename: K
authors.initials: K
authors.lastname: Christiansen
authors.forename: A
authors.initials: A
authors.lastname: Andersen
authors.forename: F
authors.initials: F
authors.lastname: Jakob
authors.forename: J
authors.initials: J
authors.lastname: Köhrle
mesh_terms: D001483:Base Sequence; D002474:Cell-Free System; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008969:Molecular Sequence Data; D010957:Plasmids; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D059004:Topoisomerase I Inhibitors; D011794:Quercetin; D011088:DNA Ligases