Novel Double-Modified Colchicine Derivatives Bearing 1,2,3-Triazole: Design, Synthesis, and Biological Activity Evaluation

Julia Krzywik; Anna Nasulewicz-Goldeman; Witold Mozga; Joanna Wietrzyk; Adam Huczyński

doi:10.1021/acsomega.1c03948

Novel Double-Modified Colchicine Derivatives Bearing 1,2,3-Triazole: Design, Synthesis, and Biological Activity Evaluation

ACS Omega. 2021 Sep 28;6(40):26583-26600. doi: 10.1021/acsomega.1c03948. eCollection 2021 Oct 12.

Authors

Julia Krzywik^{1

2}, Anna Nasulewicz-Goldeman³, Witold Mozga², Joanna Wietrzyk³, Adam Huczyński¹

Affiliations

¹ Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.
² TriMen Chemicals, Piłsudskiego 141, 92-318 Łódź, Poland.
³ Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.

Abstract

A series of 1,4-disubstituted 1,2,3-triazoles having 10-demethoxy-10-N-methylaminocolchicine core were designed and synthesized via the Cu(I)-catalyzed "click" reaction and screened for their in vitro cytotoxicity against four cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and one noncancerous cell line (BALB/3T3). Indexes of resistance (RI) and selectivity (SI) were also determined to assess the potential of the analogues to break drug resistance of the LoVo/DX cells and to verify their selectivity toward killing cancer cells over normal cells. The compounds with an ester or amide moiety in the fourth position of 1,2,3-triazole of 10-N-methylaminocolchicine turned out to have the greatest therapeutic potential (low IC₅₀ values and favorable SI values), much better than that of unmodified colchicine or doxorubicin and cisplatin. Thus, they make a valuable clue for the further search for a drug having a colchicine scaffold.