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Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives
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Cells 2018, 7(11), 216; https://doi.org/10.3390/cells7110216

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

1
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
2
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland
3
Depertment of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada
4
Depertment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
5
DIMEAS, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Turin, Italy
*
Author to whom correspondence should be addressed.
Received: 29 October 2018 / Revised: 14 November 2018 / Accepted: 14 November 2018 / Published: 19 November 2018
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Abstract

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. View Full-Text
Keywords: colchicine binding site inhibitor; tubulin-targeting agent; antimitotic agent; antiproliferative activity; thiocolchicine; natural compounds colchicine binding site inhibitor; tubulin-targeting agent; antimitotic agent; antiproliferative activity; thiocolchicine; natural compounds
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Majcher, U.; Klejborowska, G.; Kaik, M.; Maj, E.; Wietrzyk, J.; Moshari, M.; Preto, J.; Tuszynski, J.A.; Huczyński, A. Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents. Cells 2018, 7, 216.

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