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Bioorg Chem. 2020 Apr;97:103664. doi: 10.1016/j.bioorg.2020.103664. Epub 2020 Feb 13.

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

Author information

1
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland.
2
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
3
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
4
Depertment of Oncology, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
5
Depertment of Chemistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
6
Depertment of Chemistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada; DIMEAS, Politecnico di Torino, Corso Duca degli Abruzzi 24, Turin, Italy.
7
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland. Electronic address: adhucz@amu.edu.pl.

Abstract

Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.

KEYWORDS:

Anticancer activity; Mechanistic investigation; Triple-modified colchicine, Amides; Tubulin inhibitors

PMID:
32106039
DOI:
10.1016/j.bioorg.2020.103664
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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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