Novel triazolium based 11th group NHCs: synthesis, characterization and cellular response mechanisms

The novel NHC ligand precursor 1,4-bis(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide, [HTz(pNO(2)Bz)(2)] Br, has been synthesized and used in the synthesis of the corresponding metal complexes M[Tz(pNO(2)Bz)(2)] Br (M = Cu(I), Ag(I) or Au(I)). These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. The complete series of Au(I), Ag(I) and Cu(I) 1,2,4-triazole based NHC complexes has been synthesized aiming at a SAR study and at identifying the primary cellular targets accounting for their cytotoxic action. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin sensitive and resistant cells, the most efficacious antiproliferative compound being Cu(I)-NHC, which was able to promote a growth inhibitory effect up to ten times higher than that promoted by cisplatin. A detailed analysis of molecular and cellular pharmacology allowed us to elucidate the role of the metallic core in determining the biological properties. In particular, gold(I) and silver(I) NHC complexes were found to be able to hamper mammalian thioredoxin reductase (TrxR) activity in human A431 cervical cancer cells, ultimately leading to a dramatic alteration of the cellular redox state and to the induction of cell death via apoptosis. Conversely, the copper NHC complex was found to be capable of inhibiting proteasome functionality thus determining the induction of a non-apoptotic cell death pathway.