Antiproliferative activity and molecular docking of novel double-modified colchicine derivatives

Majcher, Urszula; Klejborowska, Greta; Moshari, Mahshad; Maj, Ewa; Wietrzyk, Joanna; Bartl, Franz; Tuszynski, Jack A.; Huczynski, Adam

doi:10.3390/CELLS7110192

Title

Antiproliferative activity and molecular docking of novel double-modified colchicine derivatives

Author

Majcher, Urszula

Klejborowska, Greta

Moshari, Mahshad

Maj, Ewa

Wietrzyk, Joanna

Bartl, Franz

Tuszynski, Jack A.

Huczynski, Adam

Abstract

Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein beta-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 beta-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.

Language

English

Source (journal)

Cells

Publication

2018

ISSN

2073-4409

DOI

10.3390/CELLS7110192

Volume/pages

7 :11 (2018) , 16 p.