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.