Antitumoral Gold and Silver Complexes with Ferrocenyl-Amide Phosphines

Abstract

The monosubstituted ferrocenyl-amide phosphine ligands PPh2CH2CH2NHCOFc and (PPh2CH2CH2)2NCOFc and the disubstituted ferrocenyl-amide diphosphine (PPh2CH2CH2NHCO)2Fc have been synthesized and used to prepare the gold chloride derivatives [AuCl(PPh2CH2CH2NHCOFc)], [Au2Cl2{(PPh2CH2CH2)2NCOFc}], and [Au2Cl2{(PPh2CH2CH2NHCO)2Fc}] or the silver species [Ag(OTf)(PPh2CH2CH2NHCOFc)2] and [Ag(OTf)(PPh3)(PPh2CH2CH2NHCOFc)]. In the gold complexes the chloro ligands can be easily substituted by several biologically relevant thiolates such as 2-mercaptonicotinic acid, 2-thiocytosine, 2-thiouracil, 2-mercaptopurine, and 2,3,4,6-tetra-6-acetyl-1-thiol-β-d-glucopyranosato, affording the gold phosphine thiolate derivatives. In addition, the gold phosphine thiolates of the closely related 1,1′-bis(diphenylphosphine)ferrocene ligand have been prepared in order to compare their biological activities. The antiproliferative activity of these compounds has been tested by the MTT viability assay in two murine cell lines, NIH-3T3 (mouse embryonic fibroblasts) and PC-12 (pheochromocytoma of the rat adrenal medulla), and two human cell lines, A-549 (adenocarcinomic human alveolar basal epithelial cells) and Hep-G2 (hepatocellular carcinoma). The amide-phosphine ligands are not active, whereas the chloro-gold derivatives have good antiproliferative activity in the murine cell lines and very low activity in the human cell lines. The silver complexes are less active than the gold derivatives. The gold thiolate complexes have moderate to very good cytotoxic activity for all of the ligands, showing excellent IC50 values for the thiolate complexes of the amide-phosphines PPh2CH2CH2NHCOFc and (PPh2CH2CH2N)2COFc and dppf.