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dc.contributor.author | González, Myriam | |
dc.contributor.author | Ovejero-Sánchez, María | |
dc.contributor.author | Vicente-Blázquez, Alba | |
dc.contributor.author | Álvarez, Raquel | |
dc.contributor.author | Herrero, Ana B. | |
dc.contributor.author | Medarde Agustín, Manuel | |
dc.contributor.author | González Sarmiento, Rogelio | |
dc.contributor.author | Peláez, Rafael | |
dc.date.accessioned | 2022-01-25T11:19:50Z | |
dc.date.available | 2022-01-25T11:19:50Z | |
dc.date.issued | 2021-02 | |
dc.identifier.uri | http://hdl.handle.net/10366/148383 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | We thank the people at Frigoríficos Salamanca S.A slaughterhouse for providing us with the calf brains, “Servicio General de NMR” and “Servicio General de Espectrofotometría de Masas” of the University of Salamanca for equipment. M.G. acknowledges a predoctoral fellowship from the Junta de Castilla y León (ORDEN EDU/529/2017 de 26 de junio). M.O.-S. acknowledges a predoctoral fellowship from the IBSAL (IBpredoc17/00010). A.V.-B. acknowledges a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02457). This research was funded by the Consejería de Educación de la Junta de Castilla y León (SA030U16, SA262P18 and SA116P20), co-funded by the EU’s European Regional Development Fund-FEDER, the Spanish Ministry of Science, Innovation and Universities (RTI2018-099474-BI00) and the health research program of the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness, PI16/01920 and PI20/01569) co-funded with FEDER founds. | es_ES |
dc.format.mimetype | application/pdf | |
dc.language.iso | eng | es_ES |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Tubulin | es_ES |
dc.subject | Sulfonamide | es_ES |
dc.subject | Antitumor | es_ES |
dc.subject | Taxane | es_ES |
dc.subject | Combretastatin A-4 | es_ES |
dc.subject | Breast cancer | es_ES |
dc.subject | Gynecologic cancer | es_ES |
dc.title | Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.relation.publishversion | https://doi.org/10.3390/ijms22041907 | es_ES |
dc.identifier.doi | 10.3390/ijms22041907 | |
dc.relation.projectID | SA030U16 | es_ES |
dc.relation.projectID | SA262P18 | es_ES |
dc.relation.projectID | SA116P20 | es_ES |
dc.relation.projectID | RTI2018-099474-BI00 | es_ES |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es_ES |
dc.identifier.essn | 1422-0067 | |
dc.journal.title | International Journal of Molecular Sciences | es_ES |
dc.volume.number | 22 | es_ES |
dc.issue.number | 4 | es_ES |
dc.page.initial | 1907 | es_ES |
dc.type.hasVersion | info:eu-repo/semantics/publishedVersion | es_ES |
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