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 altern...
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doaj-9bbef26d8ec54eaa829f9247145bb72d2021-02-15T00:03:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01221907190710.3390/ijms22041907Microtubule Destabilizing Sulfonamides as An Alternative to Taxane-Based ChemotherapyMyriam González0María Ovejero-Sánchez1Alba Vicente-Blázquez2Raquel Álvarez3Ana B. Herrero4Manuel Medarde5Rogelio González-Sarmiento6Rafael Peláez7Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, SpainInstituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Facultad de Farmacia, Universidad de Salamanca, 37007 Salamanca, SpainPan-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, <i>N</i>-methyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide <b>38</b>, <i>N</i>-methyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide <b>42</b>, and <i>N</i>-benzyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide <b>45</b> 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.https://www.mdpi.com/1422-0067/22/4/1907tubulinsulfonamideantitumortaxanecombretastatin A-4breast cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Myriam González María Ovejero-Sánchez Alba Vicente-Blázquez Raquel Álvarez Ana B. Herrero Manuel Medarde Rogelio González-Sarmiento Rafael Peláez |
spellingShingle |
Myriam González María Ovejero-Sánchez Alba Vicente-Blázquez Raquel Álvarez Ana B. Herrero Manuel Medarde Rogelio González-Sarmiento Rafael Peláez Microtubule Destabilizing Sulfonamides as An Alternative to Taxane-Based Chemotherapy International Journal of Molecular Sciences tubulin sulfonamide antitumor taxane combretastatin A-4 breast cancer |
author_facet |
Myriam González María Ovejero-Sánchez Alba Vicente-Blázquez Raquel Álvarez Ana B. Herrero Manuel Medarde Rogelio González-Sarmiento Rafael Peláez |
author_sort |
Myriam González |
title |
Microtubule Destabilizing Sulfonamides as An Alternative to Taxane-Based Chemotherapy |
title_short |
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_sort |
microtubule destabilizing sulfonamides as an alternative to taxane-based chemotherapy |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-02-01 |
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, <i>N</i>-methyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide <b>38</b>, <i>N</i>-methyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide <b>42</b>, and <i>N</i>-benzyl-<i>N</i>-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide <b>45</b> 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. |
topic |
tubulin sulfonamide antitumor taxane combretastatin A-4 breast cancer |
url |
https://www.mdpi.com/1422-0067/22/4/1907 |
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