A PYRIMIDO[1,6-ALPHA]BENZIMIDAZOLE THAT ENHANCES DNA CLEAVAGE MEDIATED BY EUKARYOTIC TOPOISOMERASE II - A NOVEL CLASS OF TOPOISOMERASE II-TARGETED DRUGS WITH CYTOTOXIC POTENTIAL

Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryotic cells have been described. Many of these compounds contain aromatic substituents in their C-7 ring positions. To determine whether pyrimido[1,6-alpha]benzimidazoles, a class of drugs modeled on quinolones, also display activity toward eukaryotic systems, the effects of Ro 46-7864 and Ro 47-3359 on Drosophila melanogaster topoisomerase II and Kc cells were characterized. While the former drug contains an aliphatic group (4-N-methylpiperazine) at the ring position equivalent to C-7 in quinolones, the latter compound contains an aromatic substituent (2,6-dimethylpyridine). Both pyrimido[1,6-alpha]benzimidazoles inhibited DNA relaxation catalyzed by the type II enzyme. However, only Ro 47-3359 enhanced topoisomerase II-mediated DNA cleavage and was toxic to Kc cells. At a concentration of 100 mu M, this drug approximately doubled the levels of DNA breakage in vitro and killed >50% of the initial cell population of cultures. These results strongly suggest that selected pyrimido[1,6-alpha]benzimidazoles may function as topoisomerase II-targeted drugs with cytotoxic potential.