Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand As Potential Anticancer Agents

The synthesis and characterization of a new water-soluble iminophosphorane ligand TPAN-C­(O)-2BrC6H4 (1, C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) is reported. Oxidative addition of 1 to Pd2(dba)3 affords the orthopalladated dimer [Pd­(μ-Br)­{C6H4(C­(O)­NTPA-kC,N)-2}]2 (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging chlorides can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium­(II) complexes of the type [Pd­{C6H4(C­(O)­NTPA-kC,N)-2}­(L-L)] (L-L = acac (3); S2CNMe2 (4); 4,7-diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C12H6N2(C6H4SO3Na)2 (5)), [Pd­{C6H4(C­(O)­NTPA-kC,N)-2}­(L)­Br] (L = P­(mC6H4SO3Na)3 (6); P­(3-pyridyl)3 (7)), and [Pd­(C6H4(C­(O)­NTPA)-2}­(TPA)2Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents, and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC), and DU-145 human prostate cancer cells. Compounds [Pd­(μ-Br)­{C6H4(C­(O)­NTPA-kC,N)-2}]2 (2) and [Pd­{C6H4(C­(O)­NTPA-kC,N)-2}­(acac)] (3) (which has been crystallographically characterized) display higher cytotoxicity against the above-mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin-resistant Jurkat shBak, indicating a cell death pathway that may be different from that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin, pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin faster than that of cisplatin.