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Cells. 2018 Nov 1;7(11). pii: E192. doi: 10.3390/cells7110192.

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

Author information

1
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. urszula.majcher@amu.edu.pl.
2
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. greta.klejborowska@amu.edu.pl.
3
Department of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada. moshari@ualberta.ca.
4
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland. ewa.maj@iitd.pan.wroc.pl.
5
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland. wietrzyk@iitd.pan.wroc.pl.
6
Institut für Biologie, AG Biophysikalische Chemie,Humboldt Universität zu Berlin, Invalidenstr, 42, 10099 Berlin, Germany. bartlfra@cms.hu-berlin.de.
7
Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada. jack.tuszynski@gmail.com.
8
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. adhucz@amu.edu.pl.

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.

KEYWORDS:

antimitotic agent; antiproliferative activity; colchicine binding site inhibitor; thiocolchicine; β-tubulin affinity

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