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

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

Unexpectedly High Barriers to M–P Rotation in Tertiary Phobane Complexes: PhobPR Behavior That Is Commensurate with ^tBu₂PR

The four isomers of 9-butylphosphabicyclo[3.3.1]­nonane, <i>s-</i>PhobPBu, where Bu = <i>n</i>-butyl, <i>sec</i>-butyl, isobutyl, <i>tert</i>-butyl, have been prepared. Seven isomers of 9-butylphosphabicyclo[4.2.1]­nonane (<i>a</i>₅<i>-</i>PhobPBu, where Bu = <i>n</i>-butyl, <i>sec</i>-butyl, isobutyl, <i>tert</i>-butyl; <i>a</i>₇<i>-</i>PhobPBu, where Bu = <i>n-</i>butyl, isobutyl, <i>tert</i>-butyl) have been identified in solution; isomerically pure <i>a</i>₅<i>-</i>PhobPBu and <i>a</i>₇<i>-</i>PhobPBu, where Bu = <i>n</i>-butyl, isobutyl, have been isolated. The σ-donor properties of the PhobPBu ligands have been compared using the <i>J</i>_PSe values for the PhobP­(Se)­Bu derivatives. The following complexes have been prepared: <i>trans-</i>[PtCl₂(<i>s-</i>PhobPR)₂] (R = ⁿBu (<b>1a</b>), ⁱBu (<b>1b</b>), ^sBu (<b>1c</b>), ^tBu (<b>1d</b>)); <i>trans-</i>[PtCl₂(<i>a</i>₅<i>-</i>PhobPR)₂] (R = ⁿBu (<b>2a</b>), ⁱBu (<b>2b</b>)); <i>trans-</i>[PtCl₂(<i>a</i>₇<i>-</i>PhobPR)₂] (R = ⁿBu (<b>3a</b>), ⁱBu (<b>3b</b>)); <i>trans-</i>[PdCl₂(<i>s-</i>PhobPR)₂] (R = ⁿBu (<b>4a</b>), ⁱBu (<b>4b</b>)); <i>trans-</i>[PdCl₂(<i>a</i>₅<i>-</i>PhobPR)₂] (R = ⁿBu (<b>5a</b>), ⁱBu (<b>5b</b>)); <i>trans-</i>[PdCl₂(<i>a</i>₇<i>-</i>PhobPR)₂] (R = ⁿBu (<b>6a</b>), ⁱBu (<b>6b</b>)). The crystal structures of <b>1a</b>–<b>4a</b> and <b>1b</b>–<b>6b</b> have been determined, and of the ten structures, eight show an anti conformation with respect to the position of the ligand R groups and two show a syn conformation. Solution variable-temperature ³¹P NMR studies reveal that all of the Pt and Pd complexes are fluxional on the NMR time scale. In each case, two species are present (assigned to be the syn and anti conformers) which interconvert with kinetic barriers in the range 9 to >19 kcal mol^–1. The observed trend is that, the greater the bulk, the higher the barrier. The magnitudes of the barriers to M–P bond rotation for the PhobPR complexes are of the same order as those previously reported for ^tBu₂PR complexes. Rotational profiles have been calculated for the model anionic complexes [PhobPR-PdCl₃]⁻ using DFT, and these faithfully reproduce the trends seen in the NMR studies of <i>trans-</i>[MCl₂(PhobPR)₂]. Rotational profiles have also been calculated for [^tBu₂PR-PdCl₃]⁻, and these show that the greater the bulk of the R group, the lower the rotational barrier: i.e., the opposite of the trend for [PhobPR-PdCl₃]⁻. Calculated structures for the species at the maxima and minima in the M–P rotation energy curves indicate the origin of the restricted rotation. In the case of the PhobPR complexes, it is the rigidity of the bicycle that enforces unfavorable H···Cl clashes involving the Pd–Cl groups with H atoms on the α- or β-carbon in the R substituent and H atoms in 1,3-axial sites within the phosphabicycle