Synthesis of Apoptosis-Inducing Iminophosphorane Organogold(III) Complexes and Study of Their Interactions with Biomolecular Targets

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Abstract

New stable cationic organogold(III) complexes containing the "pincer" iminophosphorane ligand (2-C(6)H(4)-PPh(2)=NPh) have been prepared by reaction of the previously described [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}Cl(2)] 1 and a combination of sodium or silver salts and appropriate ligands. The presence of the P atom in the PR(3) fragment has been used as a "spectroscopic marker" to study the in vitro stability (and oxidation state) of the new organogold complexes in solvents like dimethyl sulfoxide and water. Compounds with dithiocarbamato ligands and water-soluble phosphines of the general type [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}(S(2)CN-R(2))]PF(6) (R = Me 2; Bz 3) and [Au{kappa(2)-C,N-C(6)H(4)(PPh(2)=N(C(6)H(5))-2}(PR(3))(n)Cl]PF(6) (PR(3) = P{Cp(m-C(6)H(4)-SO(3)Na)(2)} n = 1 4, n = 2 TPA {1,3,5-triaza-7-phosphaadamantane} 5) have been synthesized and characterized in solution and in the solid state (the crystal structure of 2 has been determined by X-ray diffraction studies). Complexes 1-5 have been tested as potential anticancer agents, and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and Jurkat-T acute lymphoblastic leukemia cells. Compounds 2 and 3 are quite cytotoxic for these two cell lines. There is a preferential induction of apoptosis in HeLa cells after treatment with 1-5. However in the case of the more cytotoxic complex (2), cell death is activated because of both apoptosis and necrosis. The interactions of 1-5 with Calf Thymus DNA have been evaluated by Thermal Denaturation methods. All these complexes show no or little (electrostatic) interaction with DNA. The interaction of 2 with two model proteins (cytochrome c and thioredoxin reductase) has been analyzed by spectroscopic methods (vis-UV and fluorescence). Compound 2 manifests a high reactivity toward both proteins. The mechanistic implications of these results are discussed here.

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