Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test
Abstract Background Although the in silico predictive ability of the Ames test results has recently made remarkable progress, there are still some chemical classes for which the predictive ability is not yet sufficient due to a lack of Ames test data. These classes include simple heterocyclic compou...
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BMC
2024-11-01
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| Series: | Genes and Environment |
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| Online Access: | https://doi.org/10.1186/s41021-024-00316-6 |
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| author | Masaki Kurakami Atsushi Hakura Rika Sato Akihiro Kawade Takeshi Yamagata Naoki Koyama Dai Kakiuchi Shoji Asakura |
| author_facet | Masaki Kurakami Atsushi Hakura Rika Sato Akihiro Kawade Takeshi Yamagata Naoki Koyama Dai Kakiuchi Shoji Asakura |
| author_sort | Masaki Kurakami |
| collection | DOAJ |
| description | Abstract Background Although the in silico predictive ability of the Ames test results has recently made remarkable progress, there are still some chemical classes for which the predictive ability is not yet sufficient due to a lack of Ames test data. These classes include simple heterocyclic compounds. This study aimed to investigate the mutagenicity and structure-mutagenicity relationships for some heterocycles in the Ames test. In the present study, we selected 12 quinoline analogues containing one or two nitrogen atoms in the naphthalene ring and 12 indole analogues containing one to three nitrogen atoms in the indole ring, without any side moiety. Results The Ames test was performed with five standard bacterial strains (TA100, TA1535, TA98, TA1537, and WP2uvrA) using the pre-incubation method with and without rat liver S9. Five quinoline and two indole analogues were mutagenic. Among the five quinoline analogues, four were mutagenic in the presence of S9 mix with TA100, whereas cinnoline was mutagenic in the absence of S9 mix with TA1537. Among the two indole analogues, indazole was mutagenic in the presence and absence of S9 mix with WP2uvrA and 4-azaindole was mutagenic in the absence of S9 mix with TA1537. The mechanisms underlying the induction of mutagenesis appear to differ between quinoline and indole analogues. In addition, we performed in silico analysis of the mutagenicity of all these analogues using DEREK Nexus 6.1.1 (Lhasa Limited) and GT_EXPERT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as knowledge-based models and GT1_BMUT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as a statistical-based model. The knowledge-based model showed low sensitivity for both the quinoline and indole analogues (DEREK Nexus and GT_EXPERT: 20% for quinolines and 0% for indoles). Conversely, the statistical model showed high sensitivity (100% for both quinolines and indoles) and low specificity (43% for quinolines and 10% for indoles). Conclusion Based on the Ames test results, we proposed structural alerts noting that quinoline analogues were mutagenic when they had nitrogens in any of the positions 2, 5, 7, or 8 in addition to 1, and indole analogues were mutagenic when they had nitrogens at positions 2 or 4 in addition to 1. |
| format | Article |
| id | doaj-art-ae5e0f61d7bb47e98e5f837ed2c69d00 |
| institution | Kabale University |
| issn | 1880-7062 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Genes and Environment |
| spelling | doaj-art-ae5e0f61d7bb47e98e5f837ed2c69d002024-11-17T12:48:55ZengBMCGenes and Environment1880-70622024-11-0146111010.1186/s41021-024-00316-6Structure-mutagenicity relationships on quinoline and indole analogues in the Ames testMasaki Kurakami0Atsushi Hakura1Rika Sato2Akihiro Kawade3Takeshi Yamagata4Naoki Koyama5Dai Kakiuchi6Shoji Asakura7Global Drug Safety, Eisai Co., Ltd.Global Drug Safety, Eisai Co., Ltd.Tsukuba Division, Sunplanet Co., Ltd.Tsukuba Division, Sunplanet Co., Ltd.Quality Assurance Department, Sunplanet Co., Ltd.Global Drug Safety, Eisai Co., Ltd.Global Drug Safety, Eisai Co., Ltd.Global Drug Safety, Eisai Co., Ltd.Abstract Background Although the in silico predictive ability of the Ames test results has recently made remarkable progress, there are still some chemical classes for which the predictive ability is not yet sufficient due to a lack of Ames test data. These classes include simple heterocyclic compounds. This study aimed to investigate the mutagenicity and structure-mutagenicity relationships for some heterocycles in the Ames test. In the present study, we selected 12 quinoline analogues containing one or two nitrogen atoms in the naphthalene ring and 12 indole analogues containing one to three nitrogen atoms in the indole ring, without any side moiety. Results The Ames test was performed with five standard bacterial strains (TA100, TA1535, TA98, TA1537, and WP2uvrA) using the pre-incubation method with and without rat liver S9. Five quinoline and two indole analogues were mutagenic. Among the five quinoline analogues, four were mutagenic in the presence of S9 mix with TA100, whereas cinnoline was mutagenic in the absence of S9 mix with TA1537. Among the two indole analogues, indazole was mutagenic in the presence and absence of S9 mix with WP2uvrA and 4-azaindole was mutagenic in the absence of S9 mix with TA1537. The mechanisms underlying the induction of mutagenesis appear to differ between quinoline and indole analogues. In addition, we performed in silico analysis of the mutagenicity of all these analogues using DEREK Nexus 6.1.1 (Lhasa Limited) and GT_EXPERT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as knowledge-based models and GT1_BMUT from CASE Ultra 1.8.0.5 (MultiCASE Inc.) as a statistical-based model. The knowledge-based model showed low sensitivity for both the quinoline and indole analogues (DEREK Nexus and GT_EXPERT: 20% for quinolines and 0% for indoles). Conversely, the statistical model showed high sensitivity (100% for both quinolines and indoles) and low specificity (43% for quinolines and 10% for indoles). Conclusion Based on the Ames test results, we proposed structural alerts noting that quinoline analogues were mutagenic when they had nitrogens in any of the positions 2, 5, 7, or 8 in addition to 1, and indole analogues were mutagenic when they had nitrogens at positions 2 or 4 in addition to 1.https://doi.org/10.1186/s41021-024-00316-6Ames testMutagenicityHeterocyclic compoundsQuinolineIndoleStructure-mutagenicity relationship |
| spellingShingle | Masaki Kurakami Atsushi Hakura Rika Sato Akihiro Kawade Takeshi Yamagata Naoki Koyama Dai Kakiuchi Shoji Asakura Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test Genes and Environment Ames test Mutagenicity Heterocyclic compounds Quinoline Indole Structure-mutagenicity relationship |
| title | Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test |
| title_full | Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test |
| title_fullStr | Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test |
| title_full_unstemmed | Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test |
| title_short | Structure-mutagenicity relationships on quinoline and indole analogues in the Ames test |
| title_sort | structure mutagenicity relationships on quinoline and indole analogues in the ames test |
| topic | Ames test Mutagenicity Heterocyclic compounds Quinoline Indole Structure-mutagenicity relationship |
| url | https://doi.org/10.1186/s41021-024-00316-6 |
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