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

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

doi:10.1021/acsomega.1c03948

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.

Highlights

Colchicine 1 is a known active alkaloid that has been used for the treatment of acute gout, Behcet’s disease, or familial Mediterranean fever since ancient times
This compound occurs in the environment and is isolated mainly from Colchicum autumnale and Gloriosa superba.[1−4] Due to its antimitotic properties, its skeleton has been the subject of incessant interest of researchers involved in the search for compounds with anticancer activity
In view of the above, 1,2,3-triazoles represent a promising scaffold in the search for compounds with biological properties improved over those of the starting substances in which they could replace and mimic a certain moiety

Summary

INTRODUCTION

Colchicine 1 is a known active alkaloid that has been used for the treatment of acute gout, Behcet’s disease, or familial Mediterranean fever since ancient times. Pro-Val], in which one of the peptide bonds was replaced with a triazole ring, showed three times higher activity as tyrosinase inhibitors compared to the unmodified peptide.[25] In pantothenamides, the triazole isoster in the place of the amide moiety allowed to prevent degradation of the compounds and enhanced their antiplasmatic effect,[26] while in phenacetin conjugates, in which the discussed moiety change allowed reduction of toxicity and at the same time led to improvement of the anti-inflammatory, antinociceptive, and antipyretic effects of unmodified phenacetin.[27] It should be mentioned that the compounds containing the 1,2,3-triazole skeleton in their structure exhibit a wide spectrum of biological properties such as antimicrobial,[28,29] anticancer,[30,31] antiviral,[32,33] anti-inflammatory,[34] antitubercular,[35,36] or anti-Alzheimer’s disease.[37]

RESULTS AND DISCUSSION

CONCLUSIONS

EXPERIMENTAL SECTION

General Procedure for the Synthesis of Colchicine

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