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The structural basis of the genotoxicity of nitroarenofurans and related compounds
V Mersch-Sundermann1, H S Rosenkranz, G Klopman
1Department of Medical Microbiology and Hygiene, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany.
Abstract:
The CASE (Computer-Automated Structure Evaluation) methodology has been applied to an investigation of the basis of the genotoxicity (sfiA induction) of 79 nitroarenofurans and related molecules examined with the E. coli PQ37 genotoxicity assay (SOS chromotest). CASE identified 9 major activating structural fragments (biophores) responsible for the probability of genotoxicity (SAR). With respect to quantitative features, CASE identified 8 major molecular subunits related to the genotoxic potency (QSAR). Both the SAR as well as the QSAR analysis indicate that a nitro group on position 2 of the furan ring is important for activity provided one or more aromatic rings are attached to the furan ring, i.e. 2-nitrobenzofuran, 2-nitronaphthofuran, 2-nitroanthrafuran and 8-nitropyrenofuran. Additionally, a small substituent at position 3 of the furan ring, i.e. the methyl group of R7371, the ethyl group of R7427 and the butyl group of R7429, enhance the activity of 2-nitronaphtho[2,1-b]furan (R6597), whereas longer aliphatic chains decrease activity. Moreover, the activity of the nitro group at position 2 of the furan ring was increased by substitution of a methoxy group at position 7 of the R6597 structure. Additionally the n-octanol/water partition coefficient (log P) was found to be an important descriptor for the genotoxic potency in E. coli PQ37. Using the identified descriptors CASE correctly predicted the probability of genotoxicity of all of the genotoxicants and non-genotoxicants in the data base. The calculated genotoxic potency was equally good: 94% of all predicted results were within plus/minus one order of magnitude of the experimental result. Using CASE in the predictive mode, the program correctly predicted the probability of sfiA induction in E. coli of 95.8% of 24 "unknown" nitroarenofurans which were not part of the learning set (QSAR with r = 0.88-0.97).
Insights
The Computer-Automated Structure Evaluation (CASE) methodology identified key structural features driving genotoxicity in nitroarenofurans. This analysis accurately predicted chemical genotoxicity and potency, aiding in the assessment of novel compounds.
Area of Science:
- Computational chemistry
- Toxicology
- Structure-activity relationship (SAR) studies
Background:
- Genotoxicity of nitroarenofurans is a significant concern.
- Understanding the structural basis of genotoxicity is crucial for risk assessment.
Purpose of the Study:
- To apply the Computer-Automated Structure Evaluation (CASE) methodology to identify structural features responsible for the genotoxicity of nitroarenofurans.
- To develop predictive models for genotoxicity probability and potency.
Main Methods:
- Utilized the CASE methodology on 79 nitroarenofurans and related molecules.
- Employed the E. coli PQ37 genotoxicity assay (SOS chromotest).
- Performed quantitative structure-activity relationship (QSAR) and SAR analyses.
Main Results:
- CASE identified 9 activating structural fragments (biophores) and 8 molecular subunits related to genotoxic potency.
- A nitro group at position 2 of the furan ring, with attached aromatic rings, is critical for activity.
- Substituents at position 3 of the furan ring and the n-octanol/water partition coefficient (log P) significantly influence genotoxic potency.
- CASE accurately predicted genotoxicity for all compounds and achieved 94% accuracy within one order of magnitude for potency.
- Predictive models achieved 95.8% accuracy for unknown nitroarenofurans.
Conclusions:
- The CASE methodology effectively identifies structural determinants of nitroarenofuran genotoxicity.
- Predictive models derived from CASE are highly accurate for both genotoxicity probability and potency.
- CASE provides a valuable tool for assessing the genotoxic potential of novel chemical structures.