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Structure-activity relationships in the mutagenicity of N-substituted derivatives of phenanthrene-9,10-imine
A A Stark1, E Zeiger, S Shtelzer
1Department of Biochemistry, Tel Aviv University, Ramat Aviv, Israel.
Abstract:
A series of K-region, N-substituted phenanthrene imines were tested for mutagenicity in Salmonella typhimurium TA100. All chemicals were mutagenic in the absence of an exogenous metabolic activation system. The apparent decay times of the mutagenic species in diffusion plates and their alkylating activities were also measured. The unsubstituted phenanthrene-9,10-imine was approximately 70-fold more mutagenic than the corresponding phenanthrene-9,10-oxide. N-substitution with electron-releasing groups resulted in chemicals that were more mutagenic than those substituted with electron-withdrawing groups. The mutagenic activity of the latter group of chemicals was comparable with that of phenanthrene-9,10-oxide. Except for N-chlorophenanthrene imine, both alkylation of p-nitrothiophenol and apparent decay times in diffusion plates were inversely correlated with mutagenicity. It is hypothesized that reactivity towards p-nitrothiophenol (alkylating activity) and mutagenicity reflect different reactions, in contrast to other chemical mutagens. The results suggest that the high potency of phenanthrene imines as mutagens is possibly due to DNA binding via an aziridinium ion rather than a carbonium ion.
Insights
Phenanthrene imines are potent mutagens, showing higher activity than phenanthrene oxides. Their mutagenicity may stem from DNA binding via an aziridinium ion, not a carbonium ion.
Area of Science:
- Chemical mutagenesis
- Polycyclic aromatic hydrocarbons
- Structure-activity relationships
Background:
- Phenanthrene imines represent a class of K-region substituted polycyclic aromatic hydrocarbon derivatives.
- Their mutagenic potential and mechanisms are of significant interest in toxicology and carcinogenesis research.
Purpose of the Study:
- To evaluate the mutagenicity of K-region, N-substituted phenanthrene imines in Salmonella typhimurium TA100.
- To investigate the relationship between chemical structure, alkylating activity, and mutagenic potency.
- To elucidate the potential mechanism of DNA interaction for these compounds.
Main Methods:
- Bacterial mutagenicity testing using Salmonella typhimurium TA100.
- Measurement of apparent decay times of mutagenic species in diffusion plates.
- Assessment of alkylating activity via reaction with p-nitrothiophenol.
Main Results:
- All tested phenanthrene imines exhibited mutagenicity without exogenous metabolic activation.
- Unsubstituted phenanthrene-9,10-imine was significantly more mutagenic (approx. 70-fold) than phenanthrene-9,10-oxide.
- N-substitution with electron-releasing groups enhanced mutagenicity compared to electron-withdrawing groups.
- Mutagenicity showed an inverse correlation with alkylating activity and decay time, except for N-chlorophenanthrene imine.
Conclusions:
- Phenanthrene imines are potent mutagens, with activity influenced by N-substitution.
- The mechanism of mutagenicity may involve DNA binding through an aziridinium ion intermediate.
- Reactivity towards p-nitrothiophenol may not directly reflect the mutagenic mechanism for these compounds.