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Cells 2018, 7(11), 192; https://doi.org/10.3390/cells7110192

Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

1
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland
2
Department of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada
3
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland
4
Institut für Biologie, AG Biophysikalische Chemie, Humboldt Universität zu Berlin, Invalidenstr, 42, 10099 Berlin, Germany
5
Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
*
Author to whom correspondence should be addressed.
Received: 5 October 2018 / Revised: 24 October 2018 / Accepted: 31 October 2018 / Published: 1 November 2018
(This article belongs to the Special Issue Tubulin: Structure, Functions and Roles in Disease)
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Abstract

Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells. View Full-Text
Keywords: colchicine binding site inhibitor; β-tubulin affinity; antimitotic agent; antiproliferative activity; thiocolchicine colchicine binding site inhibitor; β-tubulin affinity; antimitotic agent; antiproliferative activity; thiocolchicine
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Majcher, U.; Klejborowska, G.; Moshari, M.; Maj, E.; Wietrzyk, J.; Bartl, F.; Tuszynski, J.A.; Huczyński, A. Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives. Cells 2018, 7, 192.

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