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Comparative study on the mutagenicity of three structurally related substituted aniline mustards in the
G Voutsinas1, A Kappas, N A Demopoulos
1Institute of Biology, National Research Center Democritus, Athens, Greece.
Abstract:
The ortho, meta and para isomers of N,N-bis(2-chloroethyl)aminocinnamic acid were tested for their ability to mutate Salmonella typhimurium strains in the Salmonella/microsome mutagenicity test. The aim of the work was to establish a structure-activity relationship between these three isomers. The drugs were found to induce base-pair substitutions, causing dose-dependent increases in his+ revertants, in strains TA100 and TA1535. The study showed that the position of the substituent groups influenced the mutagenic activity of the compounds. The ortho isomer exhibited a poorer mutagenic effect than meta and this was found to be a weaker mutagen than para. The presence of metabolic activation enzymes in the test system induced a further increase in his+ revertants, in strains TA100 and TA1535, which is consistent with the findings for melphalan, a cancer chemotherapeutic agent with a chemical structure similar to that of the isomers tested.
Insights
This study investigated the mutagenicity of N,N-bis(2-chloroethyl)aminocinnamic acid isomers in Salmonella typhimurium. The para isomer demonstrated the strongest mutagenic effect, highlighting structure-activity relationships in these compounds.
Area of Science:
- Chemical Mutagenesis
- Structure-Activity Relationship Studies
- Toxicology
Background:
- N,N-bis(2-chloroethyl)aminocinnamic acid isomers are structurally similar to melphalan, a known chemotherapeutic agent.
- Understanding the mutagenic potential of these isomers is crucial for assessing their safety and potential applications.
Purpose of the Study:
- To evaluate the mutagenic activity of ortho, meta, and para isomers of N,N-bis(2-chloroethyl)aminocinnamic acid.
- To establish a structure-activity relationship concerning the mutagenicity of these isomers.
- To investigate the influence of metabolic activation on mutagenic effects.
Main Methods:
- Utilized the Salmonella/microsome mutagenicity assay (Ames test).
- Tested mutagenicity in Salmonella typhimurium strains TA100 and TA1535.
- Assessed dose-dependent responses and the impact of metabolic activation.
Main Results:
- All tested isomers induced base-pair substitutions, indicated by an increase in his+ revertants.
- Mutagenic activity varied with isomer position: para > meta > ortho.
- Metabolic activation enhanced mutagenicity in strains TA100 and TA1535.
Conclusions:
- The position of substituent groups significantly influences the mutagenic activity of N,N-bis(2-chloroethyl)aminocinnamic acid isomers.
- The para isomer is the most potent mutagen among those tested.
- Findings align with known mutagenic mechanisms of similar compounds like melphalan.