Synthesis of apoptosis-inducing iminophosphorane organogold(III) complexes and study of their interactions with biomolecular targets.
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.
Shaik
Neha
N
Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, New York 11210, USA.
Martínez
Alberto
A
Augustin
Idline
I
Giovinazzo
Hugh
H
Varela-Ramírez
Armando
A
Sanaú
Mercedes
M
Aguilera
Renato J
RJ
Contel
María
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000187:drug effects; D004355:Drug Stability; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D010753:Phosphoranes / Q000737:chemistry; D012995:Solubility; D013880:Thioredoxin-Disulfide Reductase / Q000187:drug effects
D000970:Antineoplastic Agents; D008024:Ligands; D050607:Organogold Compounds; D010753:Phosphoranes; D045304:Cytochromes c; D013880:Thioredoxin-Disulfide Reductase