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Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities

The present study aims to report the design, synthesis, and biological activity of new ethacrynic acid (EA) analogs (6–10) obtained by the double modulation of the carboxylic acid moiety and the aromatic ring with the aim to increase the chemical reactivity of Michael acceptor of EA. All obtained co...

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Autores principales: El Abbouchi, Abdelmoula, El Brahmi, Nabil, Hiebel, Marie-Aude, Ghammaz, Hamza, El Fahime, Elmostafa, Bignon, Jérôme, Guillaumet, Gérald, Suzenet, Franck, El Kazzouli, Saïd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865193/
https://www.ncbi.nlm.nih.gov/pubmed/36677966
http://dx.doi.org/10.3390/molecules28020910
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author El Abbouchi, Abdelmoula
El Brahmi, Nabil
Hiebel, Marie-Aude
Ghammaz, Hamza
El Fahime, Elmostafa
Bignon, Jérôme
Guillaumet, Gérald
Suzenet, Franck
El Kazzouli, Saïd
author_facet El Abbouchi, Abdelmoula
El Brahmi, Nabil
Hiebel, Marie-Aude
Ghammaz, Hamza
El Fahime, Elmostafa
Bignon, Jérôme
Guillaumet, Gérald
Suzenet, Franck
El Kazzouli, Saïd
author_sort El Abbouchi, Abdelmoula
collection PubMed
description The present study aims to report the design, synthesis, and biological activity of new ethacrynic acid (EA) analogs (6–10) obtained by the double modulation of the carboxylic acid moiety and the aromatic ring with the aim to increase the chemical reactivity of Michael acceptor of EA. All obtained compounds were characterized by (1)H and (13)C NMR, IR, and high-resolution mass spectrometry. The antiproliferative activity was evaluated in vitro using MMT test, in a first step, against HL60 cell line and in a second step, on a panel of human cancer cell lines such as HCT116, A549, MCF7, PC3, U87-MG, and SKOV3, and normal cell line MRC5 in comparison with positive control doxorubicin. Among all the tested compounds, the product 8 containing a propargyl and a hydroxyl groups, allowing an intramolecular hydrogen bond with the keto group of EA, exhibited a pronounced and selective activity in a nanomolar range against HL60, A549, PC3, and MCF7 with IC(50) values of 15, 41.2, 68.7, and 61.5 nM, respectively. Compound 8 also showed a good selectivity index (SI) against HL60 and moderate SI against the other three human cancer cells (A549, PC3, and MCF7). The study of the structure-activity relationship showed that both modifications of the carboxylic group and the introduction of an intramolecular hydrogen bond are highly required to improve the antiproliferative activities. The molecular modeling studies of compound 8 revealed that it favorably binds to the glutathione S-transferase active site, which may explain its interesting anticancer activity. These new compounds have potential to be developed as novel therapeutic agents against various cancer types.
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spelling pubmed-98651932023-01-22 Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities El Abbouchi, Abdelmoula El Brahmi, Nabil Hiebel, Marie-Aude Ghammaz, Hamza El Fahime, Elmostafa Bignon, Jérôme Guillaumet, Gérald Suzenet, Franck El Kazzouli, Saïd Molecules Article The present study aims to report the design, synthesis, and biological activity of new ethacrynic acid (EA) analogs (6–10) obtained by the double modulation of the carboxylic acid moiety and the aromatic ring with the aim to increase the chemical reactivity of Michael acceptor of EA. All obtained compounds were characterized by (1)H and (13)C NMR, IR, and high-resolution mass spectrometry. The antiproliferative activity was evaluated in vitro using MMT test, in a first step, against HL60 cell line and in a second step, on a panel of human cancer cell lines such as HCT116, A549, MCF7, PC3, U87-MG, and SKOV3, and normal cell line MRC5 in comparison with positive control doxorubicin. Among all the tested compounds, the product 8 containing a propargyl and a hydroxyl groups, allowing an intramolecular hydrogen bond with the keto group of EA, exhibited a pronounced and selective activity in a nanomolar range against HL60, A549, PC3, and MCF7 with IC(50) values of 15, 41.2, 68.7, and 61.5 nM, respectively. Compound 8 also showed a good selectivity index (SI) against HL60 and moderate SI against the other three human cancer cells (A549, PC3, and MCF7). The study of the structure-activity relationship showed that both modifications of the carboxylic group and the introduction of an intramolecular hydrogen bond are highly required to improve the antiproliferative activities. The molecular modeling studies of compound 8 revealed that it favorably binds to the glutathione S-transferase active site, which may explain its interesting anticancer activity. These new compounds have potential to be developed as novel therapeutic agents against various cancer types. MDPI 2023-01-16 /pmc/articles/PMC9865193/ /pubmed/36677966 http://dx.doi.org/10.3390/molecules28020910 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
El Abbouchi, Abdelmoula
El Brahmi, Nabil
Hiebel, Marie-Aude
Ghammaz, Hamza
El Fahime, Elmostafa
Bignon, Jérôme
Guillaumet, Gérald
Suzenet, Franck
El Kazzouli, Saïd
Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title_full Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title_fullStr Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title_full_unstemmed Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title_short Improvement of the Chemical Reactivity of Michael Acceptor of Ethacrynic Acid Correlates with Antiproliferative Activities
title_sort improvement of the chemical reactivity of michael acceptor of ethacrynic acid correlates with antiproliferative activities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865193/
https://www.ncbi.nlm.nih.gov/pubmed/36677966
http://dx.doi.org/10.3390/molecules28020910
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