Discovery of ‘click’ 1,2,3-triazolium salts as potential anticancer drugs

Background: I n order to increase the effectiveness of the cancer treatment, new compounds with potential anticancer activities are synthesized and screened. We present here the screening of a new class of compounds, 1-(2-picolyl)-, 4-(2-picolyl)-, 1-(2-pyridyl)-, and 4-(2-pyridyl)-3-methyl-1,2,3-triazolium salts and ‘parent’ 1,2,3-triazole precursors. Methods: Cytotoxic activity of new compounds was determined by spectrophotometric MTT assay on several tumour and one normal cell line . Effect of selected compound to bind double stranded DNA (ds DNA) was examined by testing its influence on the thermal stability of calf thymus DNA while its influence on the cell cycle was determined by flow cytometric analysis. Generation of reactive oxygen species (ROS) was determined by addition of specific substrate 5-(and-6)-chloromethyl-2’,7’-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H 2 DCFDA). Results: Parent triazoles were largely inactive, while some of the triazolium salts were highly cytotoxic for HeLa cells. Triazolium salts exhibits high cell-type dependent cytotoxicity against different tumour cells. Selected compound (4-(4-methoxyphenyl)-3-methyl-1-(2-picolyl)-1 H -1,2,3-triazolium hexafluoro-phosphate(V) ( 2b ) was significantly more cytotoxic against tumour cells than to normal cells, with very low therapeutic index 0.130 for large cell lung carcinoma H460 cells. Additionally, this compound was similarly cytotoxic against parent laryngeal carcinoma HEp-2 cells and their drug resistant 7T subline, suggesting the potential of this compound in treatment of drug resistant cancers. Compound 2b arrested cells in the G1 phase of the cell cycle. It does not bind to ds DNA , but induced ROS in treated cells which further triggers cell death. Conclusions: Our results suggest that the ‘click’ triazolium salts are worth of further investigation as anti-cancer agents. Keywords: Triazoles, triazolium salts, anticancer activity, cell cycle, ROS