GLYCOSYLATED FLAVONES AS SELECTIVE INHIBITORS OF TOPOISOMERASE-IV

Three flavonoids which promoted Escherichia coli topoisomerase IV-depe ndent DNA cleavage were isolated from cottonseed flour and identified as quercetin 3-O-beta-D-glucose-[1,6]-O-alpha-L-rhamnose (rutin), quer cetin 3-O-beta-D-galactose-[1,6]-O-alpha-L-rhamnose, and quercetin 3-O -beta-D-glucose (isoquercitrin). The most active one (rutin) also inhi bited topoisomerase IV-dependent decatenation activity (50% inhibitory concentration, 64 mu g/ml) and induced the SOS response of a permeabl e E. coli strain. Derivatives of quercetin glycosylated at position C- 3 were shown to induce two site-specific DNA cleavages of pBR322 DNA, which were mapped by DNA sequence analysis to the gene encoding resist ance to tetracycline. Cleavage at these sites,vas hardly detectable in cleavage reactions with quercetin or fluoroquinolones. None of the th ree flavonoids isolated from cottonseeds had any stimulatory activity on E. coli DNA gyrase-dependent or calf thymus topoisomerase II-depend ent DNA cleavage, and they were therefore specific to topoisomerase IV , These results show that selective be derived from the flavone struct ure. This is the first report on a DNA topisomerase inhibitor specific for topoisomerase IV.