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Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternat...

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Autores principales: González, Myriam, Ovejero-Sánchez, María, Vicente-Blázquez, Alba, Álvarez, Raquel, Herrero, Ana B., Medarde, Manuel, González-Sarmiento, Rogelio, Peláez, Rafael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918738/
https://www.ncbi.nlm.nih.gov/pubmed/33673002
http://dx.doi.org/10.3390/ijms22041907
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author González, Myriam
Ovejero-Sánchez, María
Vicente-Blázquez, Alba
Álvarez, Raquel
Herrero, Ana B.
Medarde, Manuel
González-Sarmiento, Rogelio
Peláez, Rafael
author_facet González, Myriam
Ovejero-Sánchez, María
Vicente-Blázquez, Alba
Álvarez, Raquel
Herrero, Ana B.
Medarde, Manuel
González-Sarmiento, Rogelio
Peláez, Rafael
author_sort González, Myriam
collection PubMed
description Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.
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spelling pubmed-79187382021-03-02 Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy González, Myriam Ovejero-Sánchez, María Vicente-Blázquez, Alba Álvarez, Raquel Herrero, Ana B. Medarde, Manuel González-Sarmiento, Rogelio Peláez, Rafael Int J Mol Sci Article Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers. MDPI 2021-02-14 /pmc/articles/PMC7918738/ /pubmed/33673002 http://dx.doi.org/10.3390/ijms22041907 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
González, Myriam
Ovejero-Sánchez, María
Vicente-Blázquez, Alba
Álvarez, Raquel
Herrero, Ana B.
Medarde, Manuel
González-Sarmiento, Rogelio
Peláez, Rafael
Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title_full Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title_fullStr Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title_full_unstemmed Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title_short Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy
title_sort microtubule destabilizing sulfonamides as an alternative to taxane-based chemotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918738/
https://www.ncbi.nlm.nih.gov/pubmed/33673002
http://dx.doi.org/10.3390/ijms22041907
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