DNA-directed aniline mustards with high selectivity for adenine or guanine bases: mutagenesis in a variety of Salmonella typhimurium strains differing in DNA-repair capability.
Two closely-related aniline monomustards (1 and 2), linked to a DNA-targeting acridine chromophore by a linker chain of different length, show high selectivity for alkylation of polymer DNA. The shorter-chain derivative (2) alkylates mainly at guanine N7 sites, while the longer-chain analogue (1) reacts almost exclusively at adenine N1. The biological effects of these compounds have been studied in standard Ames Salmonella typhimurium strains in order to determine the mutagenic consequences of such well-defined DNA lesions, and the effect of DNA-repair systems on them. Both compounds caused detectable mutations in strains TA1537, TA98 or TA100 and some related strains. Mutation rates were greatly enhanced in strains carrying either a uvrB deletion or the plasmid pKM101. Frameshift mutagenesis by both compounds was completely eliminated by recA deletion, in both the presence or absence of the plasmid. The adenine-selective compound (1) appeared more sensitive to the DNA-repair defects than the guanine-selective derivative (2). Additionally, only the adenine-selective compound (1) caused statistically significant levels of detectable mutation in the repair-proficient strains TA102, TA4001 or TA4006. The bacterial mutagenesis evidence suggests that a bulky, major groove-residing adenine lesion may be more readily recognised by DNA-repair systems, and more likely to lead to a wider range of mutagenic events, than a similar guanine lesion.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland, School of Medicine, New Zealand.
Denny
W A
WA
Boritzki
T J
TJ
D000225:Adenine / Q000378:metabolism; D000478:Alkylation; D000816:Aniline Mustard / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage; D004260:DNA Repair; D006147:Guanine / Q000378:metabolism; D007364:Intercalating Agents / Q000633:toxicity*; D016297:Mutagenesis, Site-Directed; D009153:Mutagens / Q000633:toxicity*; D017354:Point Mutation; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity
D007364:Intercalating Agents; D009153:Mutagens; D006147:Guanine; D000816:Aniline Mustard; D000225:Adenine