Iminophosphoranes As Useful Precursors To Potential Transition Metal-Based Cancer Chemotherapeutics

During the past two decades, gold(III), platinum(II), palladium(II) and ruthenium(II) compounds have been investigated as potential anticancer drugs. Our group at Brooklyn College reported on the cytotoxic properties of neutral and cationic gold(III), palladium(II) and platinum(II) complexes with iminophosphoranes (IM) or iminophosphine ligands of the general formula R3P=NR\u27. These IM ligands have been very useful to synthesize and stabilize compounds of d8 transition metals which displayed higher toxicity against leukemia, prostate cancer and ovarian cancer cells when compared to normal T-lymphocytes. They also seemed to have a mode of action different from that of cisplatin. This thesis describes the synthesis of coordination and organometallic, gold(III), platinum(II), palladium(II) and ruthenium(II) complexes with different iminophosphorane ligands, the study of their stability in solution by different techniques and of their interaction with biological targets (mostly DNA and HSA). I have also included data on the biological activity of these compounds (in vitro and for selected complexes in vivo) to understand their potential as cancer chemotherapeutics. Most of these compounds have displayed excellent anticancer properties by a mode of action different from that currently accepted for cisplatin and, in some cases, have displayed a lower toxicity, better activity or better permeability in vivo. These results are described in three different chapters as summarized below. In Chapter III, I describe the synthesis and characterization of a series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent IM ligand derived from 8-aminoquinoline [Ph3P=N-C9H6N]. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [Mκ3-C,N,N-C6H4(PPh2=N-8-C9H6N}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh3 fragment. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A-549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin. The stability of cyclometallated compounds is markedly higher than that of coordination complexes. In Chapter IV, I describe the synthesis, characterization and stability studies of new organometallic gold(III) and platinum(II) complexes containing cyclometalated IM ligands. Most compounds are more cytotoxic to a number of human cancer cell lines than cisplatin. A cationic Pt(II) derivative ([Pt{κ2-C,N-C6H4(PPh2=N(C6H5)(COD)](PF6)) displays IC50 values in the sub-micromolar range. Its cell death mechanism is mainly through caspase-dependent apoptosis but it triggers caspase-independent cell death when apoptosis is blocked. Permeability studies by two different assays: in vitro caco-2 monolayers and a rat perfusion model have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100% which potentially makes it a good candidate for oral administration. Lastly in Chapter V, I describe the synthesis, characterization and stability studies of a series of organometallic ruthenium(II) complexes containing iminophosphorane ligands. These cationic compounds with chloride as counterion are highly soluble in water (70-100 mg/mL). Most compounds (especially the highly water-soluble compound- ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, non-dependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo