DNA topoisomerase inhibitors:: biflavonoids from Ouratea species

Topoisomerase inhibitors are agents with anticancer activity. 7(n)-O-Methyl-agathisflavone (I) and amentoflavone (II) are biflavonoids and were isolated from the Brazilian plants Ouratea hexasperma and O. semiserrata, respectively. These biflavonoids and the acetyl derivative of II (IIa) are inhibitors of human DNA topoisomerases I at 200 muM, as demonstrated by the relaxation assay of supercoiled DNA, and only agathisflavone (I) at 200 muM also inhibited DNA topoisomerases II-alpha, as observed by decatenation and relaxation assays. The biflavonoids showed concentration-dependent growth inhibitory activities on Ehrlich carcinoma cells in 45-h culture, assayed by a tetrazolium method, with IC50 = 24 +/- 1.4 muM for I, 26 +/- 1.1 muM for II and 10 +/- 0.7 muM for IIa. These biflavonoids were assayed against human K562 leukemia cells in 45-h culture, but only I showed 42% growth inhibitory activity at 90 muM. Our results suggest that biflavonoids are targets for DNA topoisomerases and their cytotoxicity is dependent on tumor cell type.