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 (<b>1</b>, C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) is reported. Oxidative addition of <b>1</b> to Pd₂(dba)₃ affords the orthopalladated dimer [Pd­(μ-Br)­{C₆H₄(C­(O)­NTPA-kC,N)-2}]₂ (<b>2</b>) as a mixture of <i>cis</i> and <i>trans</i> 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 <b>2</b>, 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 (<b>3</b>); S₂CNMe₂ (<b>4</b>); 4,7-diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C₁₂H₆N₂(C₆H₄SO₃Na)₂ (<b>5</b>)), [Pd­{C₆H₄(C­(O)­NTPA-kC,N)-2}­(L)­Br] (L = P­(mC₆H₄SO₃Na)₃ (<b>6</b>); P­(3-pyridyl)₃ (<b>7</b>)), and [Pd­(C₆H₄(C­(O)­NTPA)-2}­(TPA)₂Br] (<b>8</b>) are obtained as single isomers. All new complexes were tested as potential anticancer agents, and their cytotoxicity properties were evaluated <i>in vitro</i> 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 (<b>2</b>) and [Pd­{C₆H₄(C­(O)­NTPA-kC,N)-2}­(acac)] (<b>3</b>) (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, <b>3</b> is very toxic to cisplatin-resistant Jurkat shBak, indicating a cell death pathway that may be different from that of cisplatin. The interaction of <b>2</b> and <b>3</b> 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

Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

Early–late transition metal TiAu₂ compounds [(η-C₅H₅)₂Ti­{OC­(O)­CH₂PPh₂AuCl}₂] (<b>3</b>) and new [(η-C₅H₅)₂Ti­{OC­(O)-4-C₆H₄­PPh₂AuCl}₂] (<b>5</b>) were evaluated as potential anticancer agents <i>in vitro</i> against renal and prostate cancer cell lines. The compounds were significantly more effective than monometallic titanocene dichloride and gold­(I) [{HOC­(O)­RPPh₂}­AuCl] (R = −CH₂– <b>6</b>, −4-C₆H₄– <b>7</b>) derivatives in renal cancer cell lines, indicating a synergistic effect of the resulting heterometallic species. The activity on renal cancer cell lines (for <b>5</b> in the nanomolar range) was considerably higher than that of cisplatin and highly active titanocene Y. Initial mechanistic studies in Caki-1 cells <i>in vitro</i> coupled with studies of their inhibitory properties on a panel of 35 kinases of oncological interest indicate that these compounds inhibit protein kinases of the AKT and MAPKAPK families with a higher selectivity toward MAPKAPK3 (IC₅₀ <b>3</b> = 91 nM, IC₅₀ <b>5</b> = 117 nM). The selectivity of the compounds <i>in vitro</i> against renal cancer cell lines when compared to a nontumorigenic human embryonic kidney cell line (HEK-293T) and the favorable preliminary toxicity profile on C57black6 mice indicate that these compounds (especially <b>5</b>) are excellent candidates for further development as potential renal cancer chemotherapeutics

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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M₂Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin

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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M₂Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin

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

A series of gold­(III) and palladium­(II) heterometallic complexes with new iminophosphorane ligands derived from ferrocenylphosphanes [{Cp-P­(Ph₂)N-Ph}₂Fe] (<b>1</b>), [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}₂Fe] (<b>2</b>), and [{Cp-P­(Ph₂)N-CH₂-2-NC₅H₄}­Fe­(Cp)] (<b>3</b>) have been synthesized and structurally characterized. Ligands <b>2</b> and <b>3</b> afford stable coordination complexes [AuCl₂(<b>3</b>)]­ClO₄, [{AuCl₂}₂(<b>2</b>)]­(ClO₄)₂, [PdCl₂(<b>3</b>)], and [{PdCl₂}₂(<b>2</b>)]. The complexes have been evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), in human breast cancer cells (MCF7) and in a nontumorigenic human embryonic kidney cell line (HEK-293T). The highly cytotoxic trimetallic derivatives M₂Fe (M = Au, Pd) are more cytotoxic to cancer cells than their corresponding monometallic fragments. Moreover, these complexes were significantly more cytotoxic than cisplatin in the resistant A2780R and the MCF7 cell lines. Studies of the interactions of the trimetallic compounds with DNA and the zinc-finger protein PARP-1 indicate that they exert anticancer effects in vitro based on different mechanisms of actions with respect to cisplatin

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> 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

Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold­(III) and platinum­(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt­(II) derivatives <b>4</b> and <b>5</b>, which differ only in the anion, Hg₂Cl₆^2– or PF₆^– respectively, display almost identical IC₅₀ values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds <b>3</b>, <b>4</b>, and <b>5</b> can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound <b>5</b> does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of <b>5</b> by two different assays, <i>in vitro</i> 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

In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer

A series of organometallic ruthenium­(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70–100 mg/mL). Most compounds (especially highly water-soluble <b>2</b>) 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, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of <b>2</b> 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 of <b>2</b> in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo