Because of their great structural diversity and multitude of chemical properties, N-heterocyclic carbenes (NHCs) have been utilized in a variety of capacities. Most recently, NHCs have been utilized as carrier molecules for many transition metals in medicinal chemistry. Specifically, Ag(I)-NHCs have been investigated as potent antibacterial agents and chemotherapeutics and have shown great efficacy in both in vitro and in vivo studies. Ag(I)-NHC compounds have been shown to be effective against a wide range of both Gram-positive and Gram-negative bacterial strains. Many compounds have also shown great efficacy as antitumor agents demonstrating comparable or better antitumor activity than standard chemotherapeutics such as cisplatin and 5-fluorouracil. While these compounds have shown great promise, clinical use has remained an unattained goal. Current research has been focused upon synthesis of novel Ag(I)-NHC compounds and further investigations of their antibacterial and antitumor activity. This review will focus on recent advances of Ag(I)-NHCs in medicinal applications.

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

The syntheses and characterization of C 4 and C 5 substituted N,N'bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the lipophilicity of groups at the C 4 and C 5 positions plays a crucial role in modulating the efficacy against select non-small cell lung cancer cell lines tested. Compounds 11-17 were determined to be the most active against the panel of cell lines studied. Compounds 11 and 12 were examined by the National Cancer Institute's Developmental Therapeutic Program where they were tested against the NCI-60 human cancer cell line panel in a one-dose and five-dose assay. Compound 11 had high activity against the nine lung cancer lines tested while 12 had cytotoxic effects against 59 of the 60 cell lines. Compound 11 was also studied in a murine model to determine its in vivo toxicity.

A series of N,N′-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N1(N3)) and highly lipophilic substituents at the carbon atoms (C2 and C5(C6)) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin. The National Cancer Institute’s Developmental Therapeutics Program tested 1, 3–5, 10, 11, 13–18, 20–25, and 28–30 in their 60 human tumor cell line screen. Results were supportive of data observed in our lab. Compounds with hydrophobic substituents have higher anti-cancer activity than compounds with hydrophilic substituents.

Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI 50 ranging from 200 to 250 μM over a period of 1 h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer.