A pyrimido[1,6-a]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-a]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-a]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 microM, 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-a]benzimidazoles may function as topoisomerase II-targeted drugs with cytotoxic potential.
Corbett
A H
AH
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Guerry
P
P
Pflieger
P
P
Osheroff
N
N
D042462:4-Quinolones; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism*; D004269:DNA, Bacterial / Q000187:drug effects / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects; D009690:Nucleic Acid Conformation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology* / Q000633:toxicity; D013268:Stimulation, Chemical
D042462:4-Quinolones; D000890:Anti-Infective Agents; D001562:Benzimidazoles; D004269:DNA, Bacterial; D011743:Pyrimidines; D011744:Pyrimidinones; C085885:Ro 47-3359; D004250:DNA Topoisomerases, Type II