Rosario A. Vilaplana

Study of the biological effects and DNA damage exerted by a new dipalladium-Hmtpo complex on human cancer cells

The new dipalladium complex [Pd(2)(mu-mtpo-N(3),N(4))(2)(phen)(2)](NO(3))(2) (where phen=1,10-phenantroline; Hmtpo=5,7-dihydro-7-oxo-5-methyl[1,2,4]triazolopyrimidine), (Pd(2)-Hmtpo, or complex I), interacts effectively with DNA plasmid (pBS), as studied by circular dichroism spectroscopy (CD), causing large helix distortions, altering the direction of the main DNA helix axis and producing unwinding of the DNA double helix. DNA damage induced by complex I was highly significant at 2.81 microM (ovarian carcinoma TG cell line), as assessed by comet assay, a dose at which all treated nuclei showed more than 30% DNA migration to the comet tail. DNA damage effect is a consequence of genotoxicity and not a false positive response caused by cytotoxicity. In vitro cytotoxic assay on the two human tumor cell lines TG and BT-20 (breast carcinoma), shows that doses of 0.47, 1.41 and 2.81 microM produce significant antiproliferative effects after 4 days of treatment compared with control. Complex I was highly cytotoxic at 2.81 microM causing an inhibition of viable cells of 65.5%. Cisplatin (cis-DDP) exhibits lower cytotoxic activity in TG cells than dipalladium complex (a cisplatin dose of 6.67 microM inhibits 30.3%) and does not cause migration of DNA to comet tail.

Binding of Antitumor Ruthenium(III) Complexes to Plasma Proteins

Presently, there is large interest in analysing the interactions in vitro with plasma proteins of some novel antitumor ruthenium(III) complexes that are in preclinical or clinical phase. The joint application of separation and spectroscopic techniques provides valuable information on the nature and the properties of the resulting ruthenium/protein adducts. Recent work carried out in our laboratory points out that, under physiological conditions, some selected ruthenium(III) complexes bind plasma proteins tightly with a marked preference for surface imidazole groups. Representative examples of interactions of antitumor ruthenium(III) complexes with plasma proteins such as albumin and transferrin are given. Notably the antitumor ruthenium(III) complexes considered here bind proteins much tighter than DNA; it is proposed that protein binding of ruthenium(III) complexes will have a large impact on the biodistribution, the pharmacokinetics and the mechanism of action of these experimental drugs.

Solution studies of the antitumor complex dichloro 1,2-propylendiaminetetraacetate ruthenium (III) and of its interactions with proteins.

A mixed complex of ruthenium (III) with 1,2-propylendiaminetetraacetate (PDTA) and chloride--RAP hereafter--has been found to exhibit favorable anticancer properties in vivo. To get some insight into the possible mechanism of action of this ruthenium (III) complex, its solution behavior and reactivity with proteins were investigated through absorption, circular dichroism and 1H NMR spectroscopies. Under physiological conditions RAP slowly looses the two coordinated chlorine atoms to produce a number of ruthenium (III) reactive species; a description of the distribution of these species on the dependence of pH has been obtained through 1H NMR studies of the hyperfine shifted signals. Remarkably, through the different solution conditions employed in this study, the ruthenium ion always remains in the 3+ oxidation state and the PDTA ligand is always bound to the metal. Upon reaction with albumin, apotransferrin or diferric transferrin, at a 1:1 ratio, RAP rapidly binds to these proteins to produce substantially equivalent and relatively stable adducts. This behavior is tentatively interpreted in terms of a tight interaction between RAP and surface residues of these proteins. The implications of these findings for the biological action of this novel ruthenium (III) compound are discussed.

Synthesis, Structure and Antitumour Properties of a New 1,2-Propylenediaminetetraacetate-Ruthenium(III) Compound.

A novel complex formed by ruthenium (III) and the sequestering ligand 1,2-propylenediaminetetraacetic acid (PDTA) has been synthetized and characterized. The structure of the monomeric compound, studied by X-ray diffraction , shows an almost symmetric octahedral geometry around the metal ion, with two chlorine atoms in a cis conformation. The antitumour activity against a variety of murine and human cancers is reported.

The bidentate bonding mode of bis [2-oximinocyanacetamidato(2-)-N,N]nickelate(II) anion towards tetraphenylantimony (V) : unusually long Sb — O contact

Abstract The heteronuclear complex of tetraphenylantimony (V) with anion of bis (oximino-cyanoacetamidato (2-) -N,N) nickelate (II) [ (Ph4Sb) 2 {Ni (NCC (NO) C (O) NH) 2} ] 1 was synthesized and investigated by single crystal X-ray analysis. 1 was isolated as a result of the reaction between tetraphenylantimony (V) chloride and nickel (II) complex with (hydroximino) cyanoacetamide (H2aco) Na2 {Ni (aco) 2} obtained by reaction of Ni (Haco) 2 with NaOH. The crystal comprises heterometal centrosymmetric molecules (Ph4Sb) 2 {Ni (aco) 2} . The Ni atom is in a slightly distorted square planar surrounding formed by the four nitrogen atoms of deprotonated hydroximino and amide groups (Ni — Noxime 1.890 (4) , Ni — Namide 1.862 (4) A) . The ligands are situated in trans positions with respect to each other. The coordination environment of the antimony atom in the Ph4Sb+ cation is somewhat distorted trigonal bipyramidal [SbC4O] , Sb — Ceq 2.084 (5) –2.108 (5) A . All angles Ceq — Sb — Oax are less than 90°. Ph4Sb+ coordinates to the oxygen atom of C = O group (Sb — O 2.647 (3) A ) . The geometrical parameters of the CNO group indicate that it exists in the nitroso-form.

Formation of supramolecules in solution. Interaction between transition-metal complexes and water-soluble porphyrins

The rates of copper(II) insertion into water-soluble porphyrins in the presence of ethylenediamine have been studied near pH 7. Unusual kinetic profiles result which are interpreted as arising from the formation of supramolecular assemblies in solution. Confirmatory evidence for this model is provided by light scattering, conductance and temperature-variation experiments. The influences on assembly formation of reactant concentration, porphyrin charge and basicity, ionic strength, as well as buffer and electrolyte identity are reported.

Synthesis, Structure, Properties And Biological Behaviour Of The Complex [RuIV (H2L) Cl2].2H2O(H4L= 1,2-Cyclohexanediamminetetraacetic Acid)

The highly water-soluble ruthenium complex [Ru(H2L)Cl2]2H2o, in which H4L is the sequestering ligand trans-l, 2-cyclohexanediamminetetraacetic acid (cdta) has been synthesized, structurally characterized and its properties studied. The X-ray crystallographic study shows that the chelating coordinated ligand is tetradentate while the ruthenium environment is octahedral and slightly distorted, with two chloride anions coordinated in cis positions. Potentiometric, conductimetric and infrared studies confirm the presence of two free carboxylic groups, while electronic and voltammetric studies show that the central ion is Ru(IV). The testing of the cytotoxic activity of this complex against three different human cancer cell lines indicates that [Ru(H2L)Cl2].2H2O shows a remarkable and selective antiproliferative effect against the human uterine neck carcinoma HeLa and the malign adenocarcinoma ADLD, showing only a discrete turnout cell inhibition activity against colon adenocarcinoma HT-29. The important antiprotiferative behaviour of complex 1 against the human adenocarcinoma ADLD, indicates that [Ru(H2L)Cl2].2H2O might be considered as potential antineoplastic compound.

Nitrate/nitrite reductase activity of sulfido/selenido bridged dinuclear ruthenium(III) complexes.

Series of dinuclear species [Ru(2)(L)(2)(LH)(2)-mu-S(2)Cl(2)], [Ru(2)(L)(2)(LH)(4)-mu-Se(2)Cl(2)] (L=L(1)H and L(3)H) and [Ru(2)(L(2))(2)(L(2)H)-mu-Se(2)Cl(2)].2H(2)O, where L(1)H, L(2)H and L(3)H represent for 2-mercapto-5-phenyl-1,3,4-oxadiazole, 2-mercapto-benzimidazole and 2-mercapto-benzothiazole, respectively, have been prepared and characterized by their elemental analyses and spectral (IR, UV-visible, 1H NMR and FAB mass) data. The diamagnetism of these complexes are indicative of an exchange coupled dinuclear ruthenium(III) species containing S(2)(2-) and Se(2)(2-) bridges. The complexes along with free heterocycles (L(1)H-L(3)H) as well as RuCl(3) x 3H(2)0 were tested for their nitrate and nitrite reductase activities. The electrochemical behaviour of the complexes showed irreversible oxidation peaks at +(1.04-1.40) V quite comparable to those reported for sulphido bridged complexes.

Metal complexes of theophylline-7-acetic acid. Crystal structure of a nickel(II) compound containing non-coordinated theophylline-7-acetate ion

Abstract The solids obtained by interaction of theophylline-7-acetic acid with the metal ions nickel(II), cobalt(II) and palladium(II) have been studied by standard thermal and spectroscopic methods. The structure of the compound formed with nickel(II), hexaaqua nickel(II) theophylline-7-acetate tetrahydrate, has been solved by X-ray diffraction, this being the first example of a metal salt of an anionic purine derivative in which there is not a direct metal-purine bond. Powder X-ray diffraction demonstrates that the cobalt compound is isostructural to the nickel one. A trans-square planar structure with the ligand bound to the palladium via N(9) is proposed for the palladium compound [PdCl2(theophylline-7-acetic acid)2].

Physicochemical properties of the soluble porphyrin tetrakis-(4-N-methylpyridyl)-porphine encapsulated in large unilamellar vesicles

Abstract Large unilamellar vesicles (LUV) formed by egg phosphatidylcholine (PC) and cholesterol (CL), and containing encapsulated soluble porphyrin H 2 TMpyP-4 were characterized and studied by light-scattering, freeze-fracture electron microscopy and fluorescence spectroscopy. The inclusion of CL produces a remarkable increase in LUV size (average size about 120 nm) and the number of porphyrin molecules entrapped by vesicles. Relaxation effects observed in porphyrin-loaded LUV have been attributed to the interaction between encapsulated H 2 TMpyP-4 molecules and the liposome membrane, a finding confirmed by fluorescence-emission spectroscopy. This technique also demonstrates the stability and integrity of LUV subjected to electrical discharges. Porphyrin-loaded LUV scatter light four times less than empty vesicles, a phenomenon attributed to a disturbance in lipid bilayer structure.