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

N-heterocyclic carbenes (NHCs) are an interesting class of ligands with donor properties similar to phosphines. Their chemical versatility not only implies a wide variety of structural diversity and coordination modes, but also a capability to form stable complexes with a large number of transition metals with different oxidation states. An attractive feature of NHCs chemistry is the ease with which a series of structurally similar complexes with varying lipophilicity can be synthesized simply by changing the substituents on the imidazolium salt precursor. As potential anticancer drugs, metal-NHCs constitute a recent and very rapidly growing field of research: in fact NHCs have similar donor properties to phosphines and their imidazolium salt precursors are often more easily synthesized than similarly-functionalized phosphines. To explore the possible use of NHC ligands as alternatives to phosphines in the synthesis of biologically active group 11 metal complexes, here we report the synthesis and use of N-heterocyclic pre-carbene ligands functionalized with hydrophilic groups (such as esters, amides or sulfonates) in coinage metal chemistry. In particular N-heterocyclic carbene ligand precursors HImACl (1,3-bis(2-ethoxy-2-oxoethyl)-1H-imidazol-3-ium chloride), HImBCl (1,3-bis[2-(diethylamino)-2-oxoethyl]-1H-imidazol-3-ium chloride) and NaHImPrSO3 (sodium 3,3'-(1H-imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate) have been synthesized and used in the preparation of Cu(I), Ag(I) and Au(I) adducts. The cytotoxic properties of the newly synthesized NHC complexes were investigated in various human cancer cell lines, including cisplatin sensitive and resistant cells. Growth inhibitory effects were compared with those induced in human non-transformed cells. Moreover, gold(I) and silver(I) carbene complexes were evaluated for their ability to in vitro inhibit the selenoenzyme TrxR, that is recognized as the most relevant molecular target for gold(I,III) species and recently proposed as potential protein target also for silver derivatives.