Microbial mutagenic effects of the DNA minor groove binder pibenzimol (Hoechst 33258) and a series of mustard analogues.
A series of aniline mustards and half-mustards targeted to DNA by linkage (through a polymethylene chain) to the bisbenzimidazole chromophore of pibenzimol (Hoechst 33258) have been evaluated for their mutagenic properties, as estimated in three strains of Salmonella typhimurium, and for their mitotic crossing-over and petite mutagenesis activities in Saccharomyces cerevisiae strain D5. Agarose gel electrophoresis studies showed that only the derivative with the longest linker chain cross-linked DNA, with the remaining compounds being monoalkylators. The parent (non-alkylator) minor groove binding ligand (Hoechst 33258) was inactive in the bacterial strains TA98 or TA100 but weakly mutagenic in TA102, and caused neither mitotic crossing-over nor 'petite' mutagenesis in yeast. Aniline half-mustard itself (monoalkylator) was an effective base-pair substitution mutagen (events in S. typhimurium strain TA100) with some frameshift mutagenesis activity in TA98, but showed only weak effects in the yeast assays, whereas aniline mustard (cross-linker) was inactive in these bacterial systems but caused substantial amounts of mitotic crossing-over in yeast. The composite molecules studied here showed effects more characteristic of the minor groove binding chromophore than of alkylating moieties. All showed weak mutagenic activity in TA102 and none in TA98. The only compound to show significant mitotic crossing-over ability was the long-chain derivative which cross-linked DNA. For most of the compounds, the mutagenicity data provided no supportive evidence for DNA alkylation. Since other evidence suggests this does occur readily, it is likely to have a different target to that seen with untargeted aniline mustards. The significant antitumor activity and low mutagenic potential shown by these compounds make them worthy of further study.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Denny
W A
WA
D000477:Alkylating Agents / Q000378:metabolism / Q000633:toxicity*; D000816:Aniline Mustard / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003434:Crossing Over, Genetic; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004269:DNA, Bacterial / Q000187:drug effects / Q000378:metabolism; D004271:DNA, Fungal / Q000187:drug effects / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D016368:Frameshift Mutation; D008024:Ligands; D009152:Mutagenicity Tests; D009690:Nucleic Acid Conformation; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004269:DNA, Bacterial; D004271:DNA, Fungal; D004272:DNA, Mitochondrial; D008024:Ligands; D004247:DNA; D000816:Aniline Mustard; D006690:Bisbenzimidazole