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Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. T...

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Autores principales: De Luca, Michele, Occhiuzzi, Maria Antonietta, Rizzuti, Bruno, Ioele, Giuseppina, Ragno, Gaetano, Garofalo, Antonio, Grande, Fedora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176668/
https://www.ncbi.nlm.nih.gov/pubmed/35635194
http://dx.doi.org/10.1080/14756366.2022.2081845
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author De Luca, Michele
Occhiuzzi, Maria Antonietta
Rizzuti, Bruno
Ioele, Giuseppina
Ragno, Gaetano
Garofalo, Antonio
Grande, Fedora
author_facet De Luca, Michele
Occhiuzzi, Maria Antonietta
Rizzuti, Bruno
Ioele, Giuseppina
Ragno, Gaetano
Garofalo, Antonio
Grande, Fedora
author_sort De Luca, Michele
collection PubMed
description Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.
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spelling pubmed-91766682022-06-09 Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation De Luca, Michele Occhiuzzi, Maria Antonietta Rizzuti, Bruno Ioele, Giuseppina Ragno, Gaetano Garofalo, Antonio Grande, Fedora J Enzyme Inhib Med Chem Original Article Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds. Taylor & Francis 2022-05-29 /pmc/articles/PMC9176668/ /pubmed/35635194 http://dx.doi.org/10.1080/14756366.2022.2081845 Text en © 2022 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 Original Article
De Luca, Michele
Occhiuzzi, Maria Antonietta
Rizzuti, Bruno
Ioele, Giuseppina
Ragno, Gaetano
Garofalo, Antonio
Grande, Fedora
Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title_full Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title_fullStr Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title_full_unstemmed Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title_short Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
title_sort interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176668/
https://www.ncbi.nlm.nih.gov/pubmed/35635194
http://dx.doi.org/10.1080/14756366.2022.2081845
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