Synthesis and biological activity of ester- and amide-functionalized imidazolium salts and related water-soluble coinage metal N-heterocyclic carbene complexes.

N-Heterocyclic carbene (NHC) ligand precursors, namely, HIm(A)Cl [1,3-bis(2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride] and HIm(B)Cl {1,3-bis[2-(diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride}, functionalized with hydrophilic groups on the imidazole rings have been synthesized and were used in the synthesis of corresponding carbene complexes of silver(I) and copper(I), {[Im(A)]AgCl}, {[Im(A)]CuCl}, and {[Im(B)](2)Ag}Cl. Related Au(I)NHC complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} have been obtained by transmetalation using the silver carbene precursor. These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. HIm(B)Cl and the gold(I) complexes {[Im(A)]AuCl} and {[Im(B)]AuCl} were also characterized by X-ray crystallography. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin-sensitive and -resistant cells. The silver(I) complex {[Im(B)](2)Ag}Cl was found to be the most active, with IC(50) values about 2-fold lower than those achieved with cisplatin in C13*-resistant cells. Growth-inhibitory effects evaluated in human nontransformed cells revealed a preferential cytotoxicity of {[Im(B)](2)Ag}Cl versus neoplastic cells. Gold(I) and silver(I) carbene complexes were also evaluated for their ability to in vitro inhibit the enzyme thioredoxin reductase (TrxR). The results of this investigation showing that TrxR appeared markedly inhibited by both gold(I) and silver(I) derivatives at nanomolar concentrations clearly point out this selenoenzyme as a protein target for silver(I) in addition to gold(I) complexes.