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Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy
[Image: see text] Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation....
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007106/ https://www.ncbi.nlm.nih.gov/pubmed/32364386 http://dx.doi.org/10.1021/acs.jmedchem.9b02135 |
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author | Nocentini, Alessio Alterio, Vincenzo Bua, Silvia Micheli, Laura Esposito, Davide Buonanno, Martina Bartolucci, Gianluca Osman, Sameh M. ALOthman, Zeid A. Cirilli, Roberto Pierini, Marco Monti, Simona Maria Di Cesare Mannelli, Lorenzo Gratteri, Paola Ghelardini, Carla De Simone, Giuseppina Supuran, Claudiu T. |
author_facet | Nocentini, Alessio Alterio, Vincenzo Bua, Silvia Micheli, Laura Esposito, Davide Buonanno, Martina Bartolucci, Gianluca Osman, Sameh M. ALOthman, Zeid A. Cirilli, Roberto Pierini, Marco Monti, Simona Maria Di Cesare Mannelli, Lorenzo Gratteri, Paola Ghelardini, Carla De Simone, Giuseppina Supuran, Claudiu T. |
author_sort | Nocentini, Alessio |
collection | PubMed |
description | [Image: see text] Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3–22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice. |
format | Online Article Text |
id | pubmed-8007106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-80071062021-03-30 Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy Nocentini, Alessio Alterio, Vincenzo Bua, Silvia Micheli, Laura Esposito, Davide Buonanno, Martina Bartolucci, Gianluca Osman, Sameh M. ALOthman, Zeid A. Cirilli, Roberto Pierini, Marco Monti, Simona Maria Di Cesare Mannelli, Lorenzo Gratteri, Paola Ghelardini, Carla De Simone, Giuseppina Supuran, Claudiu T. J Med Chem [Image: see text] Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3–22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice. American Chemical Society 2020-05-04 2020-05-28 /pmc/articles/PMC8007106/ /pubmed/32364386 http://dx.doi.org/10.1021/acs.jmedchem.9b02135 Text en Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Nocentini, Alessio Alterio, Vincenzo Bua, Silvia Micheli, Laura Esposito, Davide Buonanno, Martina Bartolucci, Gianluca Osman, Sameh M. ALOthman, Zeid A. Cirilli, Roberto Pierini, Marco Monti, Simona Maria Di Cesare Mannelli, Lorenzo Gratteri, Paola Ghelardini, Carla De Simone, Giuseppina Supuran, Claudiu T. Phenyl(thio)phosphon(amid)ate Benzenesulfonamides as Potent and Selective Inhibitors of Human Carbonic Anhydrases II and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced Neuropathy |
title | Phenyl(thio)phosphon(amid)ate
Benzenesulfonamides
as Potent and Selective Inhibitors of Human Carbonic Anhydrases II
and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced
Neuropathy |
title_full | Phenyl(thio)phosphon(amid)ate
Benzenesulfonamides
as Potent and Selective Inhibitors of Human Carbonic Anhydrases II
and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced
Neuropathy |
title_fullStr | Phenyl(thio)phosphon(amid)ate
Benzenesulfonamides
as Potent and Selective Inhibitors of Human Carbonic Anhydrases II
and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced
Neuropathy |
title_full_unstemmed | Phenyl(thio)phosphon(amid)ate
Benzenesulfonamides
as Potent and Selective Inhibitors of Human Carbonic Anhydrases II
and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced
Neuropathy |
title_short | Phenyl(thio)phosphon(amid)ate
Benzenesulfonamides
as Potent and Selective Inhibitors of Human Carbonic Anhydrases II
and VII Counteract Allodynia in a Mouse Model of Oxaliplatin-Induced
Neuropathy |
title_sort | phenyl(thio)phosphon(amid)ate
benzenesulfonamides
as potent and selective inhibitors of human carbonic anhydrases ii
and vii counteract allodynia in a mouse model of oxaliplatin-induced
neuropathy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007106/ https://www.ncbi.nlm.nih.gov/pubmed/32364386 http://dx.doi.org/10.1021/acs.jmedchem.9b02135 |
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