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Bioorg Med Chem. 2019 Dec 1;27(23):115144. doi: 10.1016/j.bmc.2019.115144. Epub 2019 Oct 8.

Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine 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
Department of Oncology, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
4
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
5
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada.
6
Department of Oncology, 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 is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5-9 against primary ALL-5 (IC50 = 5.3-14 nM), 5, 7-9 against A549 (IC50 = 10 nM), 5, 7-9 against MCF-7 (IC50 = 11 nM), 5-9 against LoVo (IC50 = 7-12 nM), and 5, 7-9 against LoVo/DX (IC50 = 48-87 nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.

KEYWORDS:

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

PMID:
31653441
DOI:
10.1016/j.bmc.2019.115144
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