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Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation
A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin a...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580763/ https://www.ncbi.nlm.nih.gov/pubmed/33003975 http://dx.doi.org/10.1080/14756366.2020.1828401 |
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author | Guglielmi, Paolo Rotondi, Giulia Secci, Daniela Angeli, Andrea Chimenti, Paola Nocentini, Alessio Bonardi, Alessandro Gratteri, Paola Carradori, Simone Supuran, Claudiu T. |
author_facet | Guglielmi, Paolo Rotondi, Giulia Secci, Daniela Angeli, Andrea Chimenti, Paola Nocentini, Alessio Bonardi, Alessandro Gratteri, Paola Carradori, Simone Supuran, Claudiu T. |
author_sort | Guglielmi, Paolo |
collection | PubMed |
description | A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition. |
format | Online Article Text |
id | pubmed-7580763 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-75807632020-10-29 Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation Guglielmi, Paolo Rotondi, Giulia Secci, Daniela Angeli, Andrea Chimenti, Paola Nocentini, Alessio Bonardi, Alessandro Gratteri, Paola Carradori, Simone Supuran, Claudiu T. J Enzyme Inhib Med Chem Brief Report A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition. Taylor & Francis 2020-10-02 /pmc/articles/PMC7580763/ /pubmed/33003975 http://dx.doi.org/10.1080/14756366.2020.1828401 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Brief Report Guglielmi, Paolo Rotondi, Giulia Secci, Daniela Angeli, Andrea Chimenti, Paola Nocentini, Alessio Bonardi, Alessandro Gratteri, Paola Carradori, Simone Supuran, Claudiu T. Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title | Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title_full | Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title_fullStr | Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title_full_unstemmed | Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title_short | Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
title_sort | novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580763/ https://www.ncbi.nlm.nih.gov/pubmed/33003975 http://dx.doi.org/10.1080/14756366.2020.1828401 |
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