Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent
The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodext...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Beilstein-Institut
2011-11-01
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| Series: | Beilstein Journal of Organic Chemistry |
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| Online Access: | https://doi.org/10.3762/bjoc.7.182 |
| _version_ | 1818450261431025664 |
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| author | Michael Zengerle Florian Brandhuber Christian Schneider Franz Worek Georg Reiter Stefan Kubik |
| author_facet | Michael Zengerle Florian Brandhuber Christian Schneider Franz Worek Georg Reiter Stefan Kubik |
| author_sort | Michael Zengerle |
| collection | DOAJ |
| description | The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents. |
| first_indexed | 2024-12-14T20:48:29Z |
| format | Article |
| id | doaj.art-71d818271d1e4efea4b6623831b194fb |
| institution | Directory Open Access Journal |
| issn | 1860-5397 |
| language | English |
| last_indexed | 2024-12-14T20:48:29Z |
| publishDate | 2011-11-01 |
| publisher | Beilstein-Institut |
| record_format | Article |
| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj.art-71d818271d1e4efea4b6623831b194fb2022-12-21T22:47:54ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972011-11-01711543155410.3762/bjoc.7.1821860-5397-7-182Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituentMichael Zengerle0Florian Brandhuber1Christian Schneider2Franz Worek3Georg Reiter4Stefan Kubik5Fachbereich Chemie - Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany, Fax: +49-631-205-3921Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, D-80937 München, GermanyFachbereich Chemie - Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany, Fax: +49-631-205-3921Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, D-80937 München, GermanyInstitut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, D-80937 München, GermanyFachbereich Chemie - Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany, Fax: +49-631-205-3921The potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.https://doi.org/10.3762/bjoc.7.182acetylcholinesterasecyclodextrinscyclosarinneurotoxic organophosphonatesoximes |
| spellingShingle | Michael Zengerle Florian Brandhuber Christian Schneider Franz Worek Georg Reiter Stefan Kubik Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent Beilstein Journal of Organic Chemistry acetylcholinesterase cyclodextrins cyclosarin neurotoxic organophosphonates oximes |
| title | Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent |
| title_full | Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent |
| title_fullStr | Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent |
| title_full_unstemmed | Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent |
| title_short | Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent |
| title_sort | highly efficient cyclosarin degradation mediated by a β cyclodextrin derivative containing an oxime derived substituent |
| topic | acetylcholinesterase cyclodextrins cyclosarin neurotoxic organophosphonates oximes |
| url | https://doi.org/10.3762/bjoc.7.182 |
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