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

Abstract

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.

Synthesis, characterization and interaction with bovine serum albumin of cyclometallated Pd(II) complexes containing arylimine and salicylaldimine co-ligands

“…It may indicate that the substitution of ligands affects the binding of complexes with BSA. A similar effect (more than one binding site) was observed in the interaction of cyclometallated iminophosphorane complexes and HSA as well [6]. Moreover this same effect was observed in a quantitative way (by isothermal calorimetry ITC) with other coordination palladium iminophosphorane complexes [35].…”

Luminescent iminophosphorane gold, palladium and platinum complexes as potential anticancer agents

“…21 We have also reported on the cytotoxicity of coordination and organometallic Pt(II) and Pd(II) complexes with water-soluble iminophosphorane ligands. 22,23 Interestingly, we observed that some of these Pt and Pd compounds ( b – d ) were more cytotoxic than cisplatin to leukemia cell lines (both T-Jurkat and cisplatin-resistant Jurkat sh-Bak) by a mode of action different to that of cisplatin. 22,23 …”

Potential Anticancer Heterometallic Fe–Au and Fe–Pd Agents: Initial Mechanistic Insights

“…55–58 Organogold(III) complexes containing iminophosphorane (C,N-IM) ligands of the type PPh 3 =NPh displayed a high cytotoxicity in vitro against human ovarian cancer and leukemia cell lines (in some cases with IC 50 values in the nanomolar range) 55,56 while being less toxic to normal T-lymphocytes by a non-cisplatin mode of action (involving mitochondrial production of reactive oxygen species). 56 More recently, we have reported on the cytotoxicity of coordination and organometallic Pt(II) and Pd(II) complexes with water-soluble iminophosphorane ligands.…”