Silver N-heterocyclic biscarbene complexes: Potent inhibitors of thioredoxin reductase with anticancer activity in vitro and in vivo.

Silver N-heterocyclic carbene (NHC) complexes are known to form biscarbene species from monocarbene analogs in protic polar solvents. However, the effect of the respective species of silver NHC complexes on their biological activity against bacteria or cancer cells has not been systematically explored, either in vitro or in vivo. The direct and simple conversion of monocarbene silver N-heterocyclic carbene (NHC) halide complexes (NHC)AgX, (X= Cl, Br) 1a/b - 5a/b to their biscarbene analogues (NHC)2AgX 1c/d - 5c/d is reported. The biscarbenes demonstrated generally lower activity against bacteria compared to the monocarbene complexes; however, both types showed similar activity against tumor cells and a non-tumor reference cell line. Selected mono- and biscarbene complexes 3a and 3c showed similar strong inhibitory effects on thioredoxin reductase in vitro and in cellulo and had a similar level of metal uptake into A549 cells. The subsequent evaluation of their effects in vivo revealed relatively low toxicity and high antitumoral efficacy of both selected complexes in mice. The biscarbene silver organometallic 3c showed the most pronounced reduction of tumor growth in animals. The results indicate that both (NHC)AgX and (NHC)2AgX complexes trigger anticancer activity as biscarbene complexes, making this the preferred form for future metallodrug development.