Synthesis and anti-cancer screening of novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer agents

Abstract

<i>trans</i>-Cyanocombretastatin A-4 (<i>trans</i>-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2<i>H</i>)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2<i>H</i>)-1,2,3-triazole CA-4 analogues (<b>8a-i</b>, <b>9</b> and <b>11a-e</b>) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI₅₀ values in the low nanomolar range. The most potent compound, <b>8a</b>, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2<i>H</i>)-1,2,3-triazole ring system. Compound <b>8a</b> exhibited GI₅₀ values of <10 nM against 80% of the cancer cell lines in the panel. Three triazole analogues, <b>8a</b>, <b>8b</b> and <b>8g</b>, showed particularly potent growth inhibition against the triple negative Hs578T breast cancer cell line with GI₅₀ values of 10.3 nM, 66.5 nM and 20.3 nM, respectively. Molecular docking studies suggest that these compounds bind to the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine and <i>cis</i>-CA-4, and are stabilized by Van der Waals' interactions with surrounding amino acid residues. Compound <b>8a</b> was found to inhibit tubulin polymerization <i>in vitro</i> with an IC₅₀ value of 1.7 µM. The potent cytotoxicity of these novel compounds and their inhibition of tubulin dynamics make these triazole analogues promising candidates for development as anti-cancer drugs.