Discovery of 'click' 1,2,3-triazolium salts as potential anticancer drugs.
BACKGROUND
In order to increase the effectiveness of cancer treatment, new compounds with potential anticancer activities are synthesized and screened. Here we present 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 the selected compound to bind double stranded DNA (ds DNA) was examined by testing its influence on thermal stability of calf thymus DNA while its influence on 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-H2DCFDA).


RESULTS
Parent triazoles were largely inactive, while some of the triazolium salts were highly cytotoxic for HeLa cells. Triazolium salts exhibited high cell-type dependent cytotoxicity against different tumour cells. Selected compound (4-(4-methoxyphenyl)-3-methyl-1-(2-picolyl)-1H-1,2,3-triazolium hexafluorophosphate(V) (2b) was significantly more cytotoxic against tumour cells than to normal cells, with very high therapeutic index 7.69 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 did not bind ds DNA, but induced ROS in treated cells, which further triggered cell death.


CONCLUSIONS
Our results suggest that the 'click' triazolium salts are worthy of further investigation as anti-cancer agents.
Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Ivana
I
Steiner
Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Nikolina
N
Stojanovic
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.
Aljosa
A
Bolje
Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Anamaria
A
Brozovic
Department for Translational Medicine, Children's Hospital Srebrnjak, Zagreb, Croatia.
Denis
D
Polancec
Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Andreja
A
Ambriovic-Ristov
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
Marijana Radic
MR
Stojkovic
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
Ivo
I
Piantanida
Department for Oncoplastic and Reconstructive Surgery, University Hospital for Tumors, University Clinical Hospital Centre Sisters of Mercy, Zagreb, Croatia.
Domagoj
D
Eljuga
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.
Janez
J
Kosmrlj
Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.
Maja
M
Osmak
ROS; anticancer activity; cell cycle; triazoles; triazolium salts
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