Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma
Abstract Sulfur mustard (HD) alkylates biomolecules such as proteins, generating specific biomarkers. This study employs steric hindrance, electronic effects, and solvent effects through an occupancy-removal strategy to synthesize regioisomers [N1-HETE]-His and [N3-HETE]-His, overcoming isomer separ...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01479-1 |
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| author | Long Wen Zhibin Shu Li Pan Bo Chen Gang Qu Shu Geng Yuntao Yang Yan Jiang Shilei Liu |
| author_facet | Long Wen Zhibin Shu Li Pan Bo Chen Gang Qu Shu Geng Yuntao Yang Yan Jiang Shilei Liu |
| author_sort | Long Wen |
| collection | DOAJ |
| description | Abstract Sulfur mustard (HD) alkylates biomolecules such as proteins, generating specific biomarkers. This study employs steric hindrance, electronic effects, and solvent effects through an occupancy-removal strategy to synthesize regioisomers [N1-HETE]-His and [N3-HETE]-His, overcoming isomer separation challenges in conventional methods. Density functional theory (DFT) calculations revealed hexafluoroisopropanol (HFIP)’s critical role in directing HD’s regioselective alkylation: HFIP modulates steric and electronic environments to preferentially target N1 or N3 sites of histidine imidazole rings, with predictions validated experimentally. The method further enables selective detection of the isomers in HD-contaminated plasma via standard addition, advancing absolute quantification. This work not only establishes a precision synthesis platform for biomarkers but also elucidates HFIP’s unique role in imidazole regioselectivity, offering insights for medicinal chemistry and HD toxicology. These findings hold implications for HD exposure tracking, mechanism analysis, clinical diagnostics, and antidote development. |
| format | Article |
| id | doaj-art-14302e77dcc24423849a3ffd59460fb4 |
| institution | DOAJ |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-14302e77dcc24423849a3ffd59460fb42025-08-20T03:05:56ZengNature PortfolioCommunications Chemistry2399-36692025-03-01811910.1038/s42004-025-01479-1Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasmaLong Wen0Zhibin Shu1Li Pan2Bo Chen3Gang Qu4Shu Geng5Yuntao Yang6Yan Jiang7Shilei Liu8State Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianState Key Laboratory of NBC Protection for CivilianCollege of Chemistry and Environmental Engineering, Sichuan University of Science and EngineeringState Key Laboratory of NBC Protection for CivilianAbstract Sulfur mustard (HD) alkylates biomolecules such as proteins, generating specific biomarkers. This study employs steric hindrance, electronic effects, and solvent effects through an occupancy-removal strategy to synthesize regioisomers [N1-HETE]-His and [N3-HETE]-His, overcoming isomer separation challenges in conventional methods. Density functional theory (DFT) calculations revealed hexafluoroisopropanol (HFIP)’s critical role in directing HD’s regioselective alkylation: HFIP modulates steric and electronic environments to preferentially target N1 or N3 sites of histidine imidazole rings, with predictions validated experimentally. The method further enables selective detection of the isomers in HD-contaminated plasma via standard addition, advancing absolute quantification. This work not only establishes a precision synthesis platform for biomarkers but also elucidates HFIP’s unique role in imidazole regioselectivity, offering insights for medicinal chemistry and HD toxicology. These findings hold implications for HD exposure tracking, mechanism analysis, clinical diagnostics, and antidote development.https://doi.org/10.1038/s42004-025-01479-1 |
| spellingShingle | Long Wen Zhibin Shu Li Pan Bo Chen Gang Qu Shu Geng Yuntao Yang Yan Jiang Shilei Liu Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma Communications Chemistry |
| title | Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma |
| title_full | Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma |
| title_fullStr | Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma |
| title_full_unstemmed | Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma |
| title_short | Directed synthesis of N1/N3-histidine modified by 2-hydroxyethylthioethyl and identification in sulfur mustard-exposed plasma |
| title_sort | directed synthesis of n1 n3 histidine modified by 2 hydroxyethylthioethyl and identification in sulfur mustard exposed plasma |
| url | https://doi.org/10.1038/s42004-025-01479-1 |
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