[HB(pz)3]Ag(PR3) complexes as thioredoxine reductase-targeted antiproliferative agents

Different classes of silver derivatives showed a significant in vitro antitumor activity against a variety of human cancer cell lines, often higher than the corresponding activity of the reference drug, cisplatin. Among them, several silver-phosphino derivatives endowed with significative antitumor activity have been described [1]. We investigated the biological behavior of a series of cationic homoleptic silver complexes of the type [Ag(PR3)4]+, and we observed that such complexes are able to inhibit significantly TrxR (IC50 for [Ag(PTA)4](PF6) = 10.3 nM) [2] suggesting that TrxR, recognized as the most relevant molecular target for gold compounds, could be a protein target also for silver derivatives. This behavior was confirmed for other classes of cytotoxic silver derivatives in particular for water-soluble N-heterocyclic carbene complexes [3]. Stimulated by the appealing results obtained with Cu(I) [4], we moved from the cationic homoleptic silver complexes of the type [Ag(PR3)4]+, to the synthesis of neutral mixed-ligand [HB(pz)3]Ag(PR3) silver(I) complexes (PR3 = tertiary phosphine). Again, the most effective complex against a wide panel of human cancer cells, including cisplatin and multidrug-resistant sublines, namely [HB(pz)3]Ag(PPh3), showed a strong ability to inhibit thioredoxin reductase (IC50 8.3 nM). In order to find a correlation between the biological activity of silver derivatives and the nature of the phosphino ligands, detailed studies were performed on the stability of [HB(pz)3]Ag(PR3) complexes under mass spectrometric conditions.