Bacterial mutagenicity studies of DNA-intercalating aniline mustards: an insight into the mode of action of a novel class of anti-tumour drugs.
Bifunctional alkylating agents are reactive compounds which work by crosslinking DNA, but which have no special affinity for it. A series of acridine-linked aniline mustards of widely-varying alkylator reactivity (5-11), designed as DNA-directed alkylating agents, have been evaluated in various strains of Salmonella typhimurium with differing DNA repair capabilities to obtain information about their mechanism of action. The compounds showed greatly increased potency (determined as D37 values) compared with the corresponding untargeted mustards, in the repair-proficient strain TA1978+. All but the most unreactive mustards were considerably more potent (greater than 10-fold) in the corresponding repair-deficient strain TA98, indicating that DNA-crosslinking is the major cytotoxic mechanism. However, the mutagenic profile of the compounds in four Salmonella strains, particularly in the excision repair-deficient strains TA98 and TA100, suggest the compounds also form substantial levels of mutagenic monoadducts. The possibility that intercalative binding by the acridine chromophore provides an additional geometrical restraint on cross-linking by the mustard is an important facet of design which needs further study.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland School of Medicine, Private Bag, New Zealand.
Gourdie
T A
TA
Valu
K K
KK
Denny
W A
WA
D000477:Alkylating Agents / Q000633:toxicity*; D000814:Aniline Compounds / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D003432:Cross-Linking Reagents; D007364:Intercalating Agents / Q000633:toxicity*; D009152:Mutagenicity Tests; D009154:Mutation; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D007364:Intercalating Agents