Mutagenic activity of nitracrine derivatives in Salmonella typhimurium: relationship to drug physicochemical parameters, and to bacterial uvrB and recA genes and plasmid pKM101.
To determine whether it is possible to separate antitumour and mutagenic properties in the nitracrine series, a number of 4-substituted derivatives of the hypoxia-selective drug nitracrine have been evaluated for their mutagenic effects at three loci in several strains of Salmonella typhimurium differing in DNA-repair capacity (uvrB, recA, plasmid pKM101). The drugs divided into two series in terms of their biological effects. Group A compounds (nitracrine and its Cl, F, Me and OMe derivatives) were very toxic to bacteria, and uvrB and recA deletions enhanced toxicity by 10-80-fold. Mutagenic potency was high, being slightly enhanced by uvrB and reduced by recA deletions. In contrast the toxicities and mutagenic potentials of Group B compounds (COOMe, NMe2, and two other bulky amine derivatives) were reduced by at least an order of magnitude, with uvrB and recA deletions showing lesser influence. The COOMe derivative was the only compound showing greater effects at the hisC3076 locus than the hisD3052 or hisG46 loci. The data suggest that all the compounds cause mutations through intercalation and/or monoadduct formation, but only for the COOMe derivative is intercalation the dominant mode of action. Group A compounds appear to have the additional ability to cross-link DNA, a property which amounts for their high potency but which is not compatible with bulky 4-substituents. Apart from these generalizations, there was considerable variation in mutagenic efficiency (as measured by the maximum numbers of revertant colonies) within each series. Of the compounds studied, the 4-OMe derivative appears to best retain the desirable antitumour properties of nitracrine while showing greatly-reduced mutagenic potential, and is an interesting lead for further development.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Denny
W A
WA
O'Rourke
S M
SM
D000609:Aminoacridines / Q000633:toxicity*; D004260:DNA Repair; D005798:Genes, Bacterial; D066298:In Vitro Techniques; D009152:Mutagenicity Tests; D009564:Nitracrine / Q000633:toxicity*; D010957:Plasmids; D011938:Rec A Recombinases / Q000235:genetics; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D000609:Aminoacridines; D009564:Nitracrine; D011938:Rec A Recombinases