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The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site

Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. W...

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Autores principales: Boichuk, Sergei, Galembikova, Aigul, Syuzov, Kirill, Dunaev, Pavel, Bikinieva, Firuza, Aukhadieva, Aida, Zykova, Svetlana, Igidov, Nazim, Gankova, Ksenia, Novikova, Maria, Kopnin, Pavel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510300/
https://www.ncbi.nlm.nih.gov/pubmed/34641324
http://dx.doi.org/10.3390/molecules26195780
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author Boichuk, Sergei
Galembikova, Aigul
Syuzov, Kirill
Dunaev, Pavel
Bikinieva, Firuza
Aukhadieva, Aida
Zykova, Svetlana
Igidov, Nazim
Gankova, Ksenia
Novikova, Maria
Kopnin, Pavel
author_facet Boichuk, Sergei
Galembikova, Aigul
Syuzov, Kirill
Dunaev, Pavel
Bikinieva, Firuza
Aukhadieva, Aida
Zykova, Svetlana
Igidov, Nazim
Gankova, Ksenia
Novikova, Maria
Kopnin, Pavel
author_sort Boichuk, Sergei
collection PubMed
description Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. We report two novel pyrrole-based carboxamides (CAs) (CA-61 and -84) as the compounds exhibiting potent anti-cancer properties against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. The anti-cancer activity of CAs is due to their ability to interfere with the microtubules network and inhibit tubulin polymerization. Molecular docking demonstrated an efficient binding between these ligands and the colchicine-binding site on the tubulin. CA-61 formed two hydrogen bond interactions with THR 179 (B) and THR 353 (B), whereas two hydrogen bonds with LYS 254 (B) and 1 with ASN 101 (A) were identified for CA-84. The binding energy for CA-84 and CA-61 was −9.910 kcal/mol and −9.390 kcal/mol. A tubulin polymerization assay revealed a strong inhibition of tubulin polymerization induced by CA-61 and -84. The immunofluorescence data revealed the disruption of the tubulin assembly in CA-treated cancer cells. As an outcome of the tubulin inhibition, these compounds halted the cell cycle progression in the G2/M phase, leading to the accumulation of the mitotic cells, and further induced apoptosis. Lastly, the in vivo study indicated that CAs significantly inhibited the HCC1806 breast cancer xenograft tumor growth in a nude mouse model. Collectively, we identified the novel CAs as potent MTAs, inhibiting tubulin polymerization via binding to the colchicine-binding site, disrupting the microtubule network, and exhibiting potent pro-apoptotic activities against the epithelial cancer cell lines both in vitro and in vivo.
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spelling pubmed-85103002021-10-13 The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site Boichuk, Sergei Galembikova, Aigul Syuzov, Kirill Dunaev, Pavel Bikinieva, Firuza Aukhadieva, Aida Zykova, Svetlana Igidov, Nazim Gankova, Ksenia Novikova, Maria Kopnin, Pavel Molecules Article Microtubule targeting agents (MTAs) that interfere with the dynamic state of the mitotic spindle are well-known and effective chemotherapeutic agents. These agents interrupt the microtubule network via polymerization or depolymerization, halting the cell cycle progression and leading to apoptosis. We report two novel pyrrole-based carboxamides (CAs) (CA-61 and -84) as the compounds exhibiting potent anti-cancer properties against a broad spectrum of epithelial cancer cell lines, including breast, lung, and prostate cancer. The anti-cancer activity of CAs is due to their ability to interfere with the microtubules network and inhibit tubulin polymerization. Molecular docking demonstrated an efficient binding between these ligands and the colchicine-binding site on the tubulin. CA-61 formed two hydrogen bond interactions with THR 179 (B) and THR 353 (B), whereas two hydrogen bonds with LYS 254 (B) and 1 with ASN 101 (A) were identified for CA-84. The binding energy for CA-84 and CA-61 was −9.910 kcal/mol and −9.390 kcal/mol. A tubulin polymerization assay revealed a strong inhibition of tubulin polymerization induced by CA-61 and -84. The immunofluorescence data revealed the disruption of the tubulin assembly in CA-treated cancer cells. As an outcome of the tubulin inhibition, these compounds halted the cell cycle progression in the G2/M phase, leading to the accumulation of the mitotic cells, and further induced apoptosis. Lastly, the in vivo study indicated that CAs significantly inhibited the HCC1806 breast cancer xenograft tumor growth in a nude mouse model. Collectively, we identified the novel CAs as potent MTAs, inhibiting tubulin polymerization via binding to the colchicine-binding site, disrupting the microtubule network, and exhibiting potent pro-apoptotic activities against the epithelial cancer cell lines both in vitro and in vivo. MDPI 2021-09-24 /pmc/articles/PMC8510300/ /pubmed/34641324 http://dx.doi.org/10.3390/molecules26195780 Text en © 2021 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
Boichuk, Sergei
Galembikova, Aigul
Syuzov, Kirill
Dunaev, Pavel
Bikinieva, Firuza
Aukhadieva, Aida
Zykova, Svetlana
Igidov, Nazim
Gankova, Ksenia
Novikova, Maria
Kopnin, Pavel
The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title_full The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title_fullStr The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title_full_unstemmed The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title_short The Design, Synthesis, and Biological Activities of Pyrrole-Based Carboxamides: The Novel Tubulin Inhibitors Targeting the Colchicine-Binding Site
title_sort design, synthesis, and biological activities of pyrrole-based carboxamides: the novel tubulin inhibitors targeting the colchicine-binding site
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510300/
https://www.ncbi.nlm.nih.gov/pubmed/34641324
http://dx.doi.org/10.3390/molecules26195780
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