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Structure-mutagenicity relationships of four amino-imidazonaphthyridines and imidazoquinolines
R Vikse1, F T Hatch, N W Winter
1Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California, USA.
Abstract:
We tested four isomeric imidazonaphthyridines and one imidazoquinoline compound for mutagenic activity in the Ames/Salmonella mutagenicity assay, using strain TA98 and strain YG1024, an analogue of strain TA98 with elevated O-acetyltransferase levels. Their potency was related to calculated electronic parameters. Five compounds with a linear arrangement of 3 rings showed a positive response in strain YG1024. Compound 2 (1-methylimidazo[4,5-b][1,7]naphthyridin-2-amine) is the most mutagenic in both strains, giving specific activities of about 200 and 30 revertants per microgram in strains YG1024 and TA98, respectively. Three of the compounds were weak mutagens, giving a positive dose-response only in strain YG1024, with 3-5 revertants per microgram. A higher response of all five compounds in strain YG1024 as opposed to TA98 indicates that they require O-acetyltransferase activity for their metabolism. Mutagenic potencies in strain YG1024 were positively correlated to the energy of the LUMO (lowest unoccupied molecular orbital) of the nitrenium ion.
Insights
Five novel heterocyclic compounds were evaluated for mutagenicity. Compound 2 demonstrated the highest mutagenic potential, requiring O-acetyltransferase activity for metabolic activation, and its potency correlated with electronic parameters.
Area of Science:
- Medicinal Chemistry
- Toxicology
- Computational Chemistry
Background:
- Heterocyclic compounds are widely studied for their biological activities.
- Mutagenicity testing is crucial for assessing the safety of chemical compounds.
- Structure-activity relationships help in understanding and predicting compound efficacy.
Purpose of the Study:
- To evaluate the mutagenic activity of four isomeric imidazonaphthyridines and one imidazoquinoline.
- To correlate the mutagenic potency with calculated electronic parameters.
- To investigate the role of O-acetyltransferase in the metabolic activation of these compounds.
Main Methods:
- Ames/Salmonella mutagenicity assay using strains TA98 and YG1024.
- Testing of five specific heterocyclic compounds.
- Calculation of electronic parameters, including LUMO energy of the nitrenium ion.
Main Results:
- Five compounds with a linear 3-ring arrangement showed mutagenic activity in strain YG1024.
- Compound 2 (1-methylimidazo[4,5-b][1,7]naphthyridin-2-amine) was the most potent mutagen.
- All tested compounds exhibited higher mutagenicity in YG1024 than in TA98, indicating a requirement for O-acetyltransferase.
- Mutagenic potency in YG1024 positively correlated with the LUMO energy of the nitrenium ion.
Conclusions:
- The tested imidazonaphthyridines and imidazoquinoline derivatives possess mutagenic potential.
- O-acetyltransferase activity is essential for the mutagenicity of these compounds.
- Electronic parameters, specifically LUMO energy, can predict the mutagenic potency.