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Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents

Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a seri...

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Autores principales: Majcher, Urszula, Klejborowska, Greta, Kaik, Magdalena, Maj, Ewa, Wietrzyk, Joanna, Moshari, Mahshad, Preto, Jordane, Tuszynski, Jack A., Huczyński, Adam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262455/
https://www.ncbi.nlm.nih.gov/pubmed/30463236
http://dx.doi.org/10.3390/cells7110216
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author Majcher, Urszula
Klejborowska, Greta
Kaik, Magdalena
Maj, Ewa
Wietrzyk, Joanna
Moshari, Mahshad
Preto, Jordane
Tuszynski, Jack A.
Huczyński, Adam
author_facet Majcher, Urszula
Klejborowska, Greta
Kaik, Magdalena
Maj, Ewa
Wietrzyk, Joanna
Moshari, Mahshad
Preto, Jordane
Tuszynski, Jack A.
Huczyński, Adam
author_sort Majcher, Urszula
collection PubMed
description Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.
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spelling pubmed-62624552018-12-03 Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents Majcher, Urszula Klejborowska, Greta Kaik, Magdalena Maj, Ewa Wietrzyk, Joanna Moshari, Mahshad Preto, Jordane Tuszynski, Jack A. Huczyński, Adam Cells Article Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin. MDPI 2018-11-19 /pmc/articles/PMC6262455/ /pubmed/30463236 http://dx.doi.org/10.3390/cells7110216 Text en © 2018 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
Majcher, Urszula
Klejborowska, Greta
Kaik, Magdalena
Maj, Ewa
Wietrzyk, Joanna
Moshari, Mahshad
Preto, Jordane
Tuszynski, Jack A.
Huczyński, Adam
Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title_full Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title_fullStr Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title_full_unstemmed Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title_short Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
title_sort synthesis and biological evaluation of novel triple-modified colchicine derivatives as potent tubulin-targeting anticancer agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262455/
https://www.ncbi.nlm.nih.gov/pubmed/30463236
http://dx.doi.org/10.3390/cells7110216
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