Vito Scarcia

Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A

The influence of chemical stability on the antimetastatic ruthenium(III) compound imidazolium trans-imidazoletetrachlorodimethylsulphoxideruthenium(III) (NAMI-A) in aqueous solution was studied both in vitro and in vivo. The loss of dimethyl-sulphoxide (DMSO) ligand from the compound was tested by using a NAMI-A solution acidified with HCl at pH 3.0 and aged for 0, 4, 8 and 24 h prior to intraperitoneal (i.p.) injection into CBA mice bearing advanced MCa mammary carcinoma. The activity of NAMI-A on lung metastases showed no change even after the loss of DMSO ligand from up to 50% of the molecules. The reduction of NAMI-A did not modify the number of KB cells blocked in the S+G2M phases, independent of whether the reduction occurred outside the cells or after loading the cells with the compound prior to treatment with the reductants (ascorbic acid, glutathione or cysteine). In vivo, the complete reduction of NAMI-A with equivalent amounts of ascorbic acid, glutathione or cysteine prior to administration to mice bearing advanced MCa mammary carcinoma was more active than NAMI-A alone. The data show that NAMI-A, although undergoing a series of chemical modifications, maintains its antimetastatic activity in a broad range of experimental conditions.

Heteropolymetallic complexes of 1,1′-bis(diphenylphosphino)ferrocene (dppf). IV. Solvolytic behavior and cytostatic properties towards the KB cell-line of dppf and 1,2-bis(diphenylphosphino)ethane cis-complexes of Pt(II) and Pd(II)

Abstract The novel cis-platinum(II) complexes [(dppe)Pt(μ-OH)]2(BF4)2 and [(dppe)Pt(DMF)2](BF4)2 have been prepared and characterized by 31P NMR, together with cis-[(dppe)Pt(μ-Cl)]2(BF4)2, both in poorly and strongly coordinating solvents (dppe = 1,2-bis(diphenylphosphino)ethane). All these complexes and their dppf analogs (dppf = 1,1′-bis(diphenylphosphino)ferrocene) as well as (dppf)PtCl2, (dppe)PtCl2, (dppf)PdCl2, [(dppf)Pd(μ-Cl)]2(BF4)2 and [(dppf)Pd(μ-OH)]2(BF4)2 have been tested as antiproliferating agents towards Eagles KB cell-line. Their activity is compared with that of free diphosphine ligands. For Pt(II) complexes, the ID50 figures are found to be higher than those observed for free dppf and dppe. On the contrary, the activity of the palladium dppf complexes is substantially identical to that of free diphosphine.

Palladium(II) complexes of dialkyl alpha-Anilinobenzylphosphonates. Synthesis, characterization, and cytostatic activity.

The new palladium (II) halide complexes with diethyl and dibutyl esters of (alpha-anilino-N-benzyl) phosphonic acid and diethyl and dibutyl esters of [alpha-(4-benzeneazoanilino)-N-benzyl] phosphonic acid have been prepared and studied. All organophosphorus ligands form dihalide complexes, trans-Pd(L)2X2(X = Cl or Br), with monodentate N-bonded ligand through the anilinobenzyl nitrogen in (alpha-anilino-N-benzyl) phosphonate complexes and through the azo nitrogen in [alpha-(4-benzeneazoanilino)-N-benzyl] phosphonate complexes, respectively, without participation of the phosphoryl group. Azobenzene containing ligands by ortho-metallation also form binuclear organo-palladium complexes, [Pd(L-H)Cl]2, with the metal-metal chloro bridge. The complexes have been identified and characterized by elemental analysis, infrared and 1H NMR, as well as by magnetic and conductometric measurements. All were tested in vitro for their cytostatic activity against KB and L1210 tumor cell lines. The results show that these complexes inhibit the multiplication of these tumor cells, but only the dichloro adduct of diethyl [alpha-(4-benzeneazoanilino)-N-benzyl] phosphonate was found to have activity comparable to that of the antitumor drug cisplatin.

Five-membered [C,N] and [N,O] metallocyclic complexes of palladium(II) with monoalkyl [α-(4-benzeneazoanilino)-N-benzyl]phosphonates: synthesis, characterization and antitumour activity

Abstract The synthesis, spectroscopic and biological properties of the novel palladium(II) complexes with monoethyl (HL1) and monobutyl (HL2) esters of [α-(4-benzeneazoanilino)- N -benzyl]phosphonic acid, have been prepared and studied. These potential polydentate ligands form two types of metallocyclic compounds, those with [C,N] and [N,O] five-membered chelate rings. The former are cyclopalladated chloro-bridged binuclear complexes, [PdL(μ-Cl)] 2 , in which the deprotonated ligand undergoes palladation at the azo nitrogen and the ortho -carbon, while the latter mononuclear complexes, PdL 2 , contain the organophosphorus ligand bonded through the aniline nitrogen and the deprotonated phosphonic acid oxygen. The complexes were identified and characterized by elemental analysis, magnetic and conductance measurements as well as by IR, 1 H, 13 C and 31 P nuclear magnetic resonance and ESI-mass spectroscopic studies. The in vitro antitumour activity of all the complexes was evaluated against the human KB cell line as a preliminary screening for their biological activity. The coordination behaviour of monoalkyl benzeneazophosphonates as well as the spectral and biological properties of their complexes were compared with the results reported for the corresponding dialkyl phosphonates and their palladium(II) complexes.

Preparation, characterization and activity of palladium(II) halide complexes with diethyl 8-quinolylmethylphosphonate (8-dqmp). X-ray crystal structure of [8-dqmpH]2[PdCl4]·2H2O and [8-dqmpH]2[Pd2Br6]

Abstract The synthesis, spectroscopic and biological properties of the novel palladium(II) halide complexes with diethyl 8-quinolylmethylphosphonate (8-dqmp) have been reported. It was shown that the square planar complexes trans-[Pd(8-dqmp)2X2] were obtained by reaction of 8-dqmp with PdX42− (XCl, Br) in the neutral ethanolic/aqueous solution. In the HX acidic medium the quinolinium salt complexes [8-dqmp H]2[PdX4] were isolated. They were converted by heating in methanol into the corresponding hexahalodipalladium salt complexes [8-dqmpH]2[Pd2X6]. The new complexes were characterized on the basis of elemental and thermogravimetric analysis, magnetic and conductance measurements, by the IR and 1H NMR spectra and some X-ray crystal structure determinations. The complexes were tested for their cytostatic activity on KB and L1210 cell lines. The coordination behaviour of 8-dqmp as well as the spectral and biological properties of its complexes were compared with the results reported for the diethyl ester of 2-quinolylmethylphosphonic acid (2-dqmp) and its palladium(II) halide complexes. The molecular structures of the complexes [8-dqmpH]2[PdCl4]·2H2O (3) and [8-dqmpH]2[Pd2Br6] (6) have been fully characterized by X-ray diffraction studies. The crystals of both complexes are triclinic, space group P1, Z=2, with lattice parameters for 3: a=9.438(2), b=9.481(2), c=11.082(2) A, α=83,4(1), β=107.5(1), γ=77.0(1)°, the final R factors are R=0.0481 and R′=0.0551 for 3208 observed diffractometer collected reflections; and for 6: a=11.943(2), b=10.644(2), c=8.873(2) A, α=102.08(2), β=85.56(2), γ=69.54(2)°, the final R factors are R=0.0725 and R′=0.0804 for 2584 observed diffractometer collected reflections. The structure of 3 is composed of the square planar PdCl42− anion lying in a centre of symmetry (average PdCl=2.330 A), of two quinotinium phosphonate cations and two water molecules. The structure of 6 consists of two quinolinium moieties as a cationic part separated by the Pd2Br6 centrosymmetric dianionic dimer.

Spectroscopic and biological properties of palladium(II) complexes of ethyl 2-quinolylmethylphosphonate.

Spectroscopic (1H NMR, UV-visible) and biological (cytostatic, antiviral activity) studies of palladium(II) complexes of monoethyl 2-quinolymethylphosphonate (2-Hmqmp): dihalide adducts trans-Pd(2-Hmqmp)2X2, chelate Pd(2-mqmp)2.2H2O and ion-pair salt complexes [2-H2mqmp]+[Pd(2-Hmqmp)X3]- (X = Cl, Br), have been carried out in order to determine structural and biological properties of these biologically interesting complex compounds. The complexes were evaluated in vitro for their cytostatic activity against murine L1210 and human KB and T-lymphoblast Molt4/C8 and CEM/0 cell lines, and the results obtained were compared with those obtained for the complexes of diethyl 2-quinolylmethylphosphonate (2-dqmp). The L1210 cell was the most responsive line and complexes of diester 2-dqmp were more active than complexes of monoester 2-Hmqmp. A good relationship was observed between the cytostatic activity of the complexes and their lypophilicity or solubility. Some complexes exhibited significant cell growth inhibitory effects, but none of the them was more cytostatic than cisplatin. Both 2-dqmp and 2-Hmqmp complexes were also evaluated in vitro for their antiviral activity in different assay systems, comprising a broad spectrum of DNA and RNA viruses, but no specific antiviral effects were noted. In addition, the complexes did not show any specific anti-HIV activity.

Preparation, characterization and activity of palladium(II) halide complexes with diethyl 2-quinolylmethylphosphonate (2-dqmp). X-Ray crystal structures of trans-[Pd(2-dqmp)2X2](X = Cl or Br)

A series of new palladium(II) halide complexes with diethyl 2-quinolylmethylphosphonate (2-dqmp) were prepared and studied. Two types of square-planar palladium dihalide complexes, trans-[Pd(2-dqmp)2X2] with the N-bonded monodentate ligand and cis-[Pd(2-dqmp)X2] where dqmp acts as a bidentate N,O-bonded chelate ligand, could be obtained by reaction of 2-dqmp with [PdX4]2–(X = Cl or Br) in neutral methanolic-aqueous solution. The ion-pair salt complexes, [2-Hdqmp]2[PdX4], containing the protonated quinoline ligand as cation and the square-planar tetrahalogenopalladate complex as anion, were isolated upon treatement of the ethanolic–aqueous solution with HX. The new complexes were identified and characterized by elemental and thermogravimetric analysis, magnetic and conductometric measurements, and by infrared and 1H NMR spectral studies. All were tested for cytostatic activity on KB and L1210 cell lines, but only [Pd(2-dqmp)2Br2]2 displayed a significant anti-tumour effect in both systems. The molecular structures of the complexes [Pd(2-dqmp)2X2](X = Cl, 1; Br, 2) were determined by single-crystal X-ray analysis. The crystals are triclinic, space group P, Z= 2, with other parameters: 1, a= 10.209(3), b= 9.812(3), c= 8.949(2)A, α= 78.36(2), β= 94.82(2), γ= 111.60(2)°, R= 0.0598, and R′= 0.0648 for 2982 observed reflections; 2, a= 10.502(3), b= 9.405(3), c= 9.009(3)A, α= 72.00(2), β= 103.96(2), γ= 100.63(2)°, R= 0.0574, and R′= 0.0614 for 2033 observed reflections. Each complex has a trans square-planar structure, the palladium being co-ordinated by two halogen and two nitrogen atoms and lying at a centre of symmetry.

Tumour cell uptake of the metastasis inhibitor ruthenium complex NAMI-A and its in vitro effects on KB cells

Abstract Purpose. The uptake of NAMI-A (imidazolium trans-imidazoledimethylsulphoxidetetrachlororuthenate) by KB cells in vitro was compared with the effects of this compound on the cell cycle phase distribution of the cells. Methods. NAMI-A uptake was determined by flameless atomic absorption spectroscopy, and the cell cycle phase distribution was determined by flow cytometry. Results. NAMI-A uptake was proportional to its concentration in the incubation medium. The use of a number of incubation conditions showed that NAMI-A uptake from MEM was independent of the presence of serum and dependent on the presence of amino acids in the incubation medium, and that NAMI-A uptake was markedly higher when the cells were incubated in PBS. The uptake increase observed in PBS did not occur when the cells were kept at 0–4°C, suggesting the presence of active transportation of NAMI-A into cells. In addition, the presence of divalent cations such as Ca2+ and Mg2+, appeared to facilitate NAMI-A uptake. The anionic substance transport inhibitor probenecid significantly reduced the active transportation of NAMI-A into cells. The effects of NAMI-A on cell cycle distribution were strictly dependent on its uptake by tumour cells and not on its extracellular concentration. Conclusions. These findings suggest the interaction of NAMI-A with biological components resulting in possible consequences for the distribution of the compound itself. Furthermore, NAMI-A enters tumour cells both by passive diffusion and by active transportation.

Complexes of platinum(II) halides with dithiocarbamic esters

Abstract Platinum(II) halides form either 1:1 or 1:2 complexes with dithiocarbamic esters (R 2 NC(S)SR′). Complexes of both stoichiometries have been obtained with the ligands TMDT (R  R′  Me) and DMDTE (R  Me; R′  Et), whereas with TEDT (R  R′  Et) only the 1:1 adducts were isolated. From IR spectra the complexes of formula PtL- 2 X 2 (L = TMDT, DMDTE; X = Cl, Br, I) have a trans square planar configuration by two halide and two thiocarbonyl sulfur atoms. In the complexes of formula PtLX 2 , for which a cis square planar configuration is suggested, the ligands act probably as bidentate through either thiocarbonyl or thioether sulfur. All the complexes have been tested for cytostatic activity on KB cells.

Depressive effects of Chamomilla recutita (L.) Rausch, tubular flowers, on central nervous system in mice*

Summary A lyophilized infusum of tubular flowers of Chamomilla recutita (L) Rausch ( matricaria chamomilla L.), administered i.p. in mice, was investigated in order to verify its action on central nervous system. Basal motility was dose dependently decreased, with 92% of reduction at the dose of 360 mg/kg, without involving motor coordination and muscle relaxation. Exploratory and motor activities registered in the hole-board test, were significantly decreased. A mild hypnogenic effect was displayed at 160 and 320 mg/kg, hexobarbital-induced sleep being significantly potentiated. No toxicity signs were observed at 1440 mg/kg. It was concluded that the camomile effectively displayed a depressive action on the central nervous system.