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J. PARMACOL. EXP. THER.

Presented platinum(II) complexes with phosphonate ligands represent structurally and biologically interesting class of compounds. Depending on the reaction conditions, various types of complexes of the same ligand can be obtained. Furthermore, complexes of 8-dqmp show medium cytostatic activity. Synthesis of new structurally different phosphonate ligands and their palladium as well as platinum complexes could be helpfull in elucidating rather complicated structure-activity relationship for these kind of compounds.

There has been a continued interest in the chemistry and biochemistry of phosphonic and aminophosphonic acid derivatives because of their wide range of biological and pharmacological properties, with possible application from medicine to agriculture. Another interesting aspect regarding this kind of compounds arises from their ability of forming metal complexes, which might be also of interest in living systems. In this field our systematic study is directed to platinum(II) and palladium(II) complexes of quinoline and aniline-based alkyl phosphonates, which might be of interest as potent antitumor agents [1, 2]. In this report we describe the synthesis, spectroscopic analysis and biological properties of platinum(II) and palladium(II) complexes of monoethyl quinolyl-8-ylmethylphosphonate. This organophosphorus ligand depending on reaction conditions forms neutral and ionic metal complexes. In the basic media acts as a bidentate ligand through the quinoline nitrogen and the deprotonated phosphonic acid group, while under acidic conditions are formed the quinolinium tetrahaloplatinum, tetrahalopalladium, trihalopalladium and hexahalodipalladium salt complexes, respectively. All complexes were evaluated for their in vitro cytostatic activity in an epidermoid human carcinoma (KB) and murine leukaemia (L1210) cell lines. The results obtained are compared with those obtained for the platinum(II) and palladium(II) complexes of the corresponding dialkyl esters of quinolyl-8-ylmethylphosphonate and discussed with respect to their structure-activity relationship.

Following the discovery of the cytostatic activity of cisplatin and its analogues, there is a continuing interest in the development of new platinum-based anticancer drugs with improved cytotoxicity and therapeutic properties. The studies on this type of compounds included also the substitution of platinum by its homologue palladium with similar coordination behavior in order to investigate the effects of the metal on the structural and biochemical properties of the complexes. Our systematic study is directed to palladium and platinum complexes of quinoline and aniline-based alkyl phosphonates as an effort to obtain metal complexes with potential antitumor and antiviral activity. We report here the synthesis, some spectroscopic properties (IR, 1H NMR, MS) and biological evaluation of new platinum(II) complexes of diethyl 8-quinolylmethylphosphonate (8-dqmp). The cytostatic activity of complexes was assayed in vitro on epidermoid human carcinoma KB, murine leukemia L1210/0 and human T-lymphoblast Molt4/C8 and CEM cell lines, and the antiviral assays were carried out in vitro in HEL, Vero and HeLa cell cultures infected with a variety of DNA and RNA viruses. The results obtained are compared with those of the palladium(II) chloride, bromide and acetate complexes of the same ligand and are discussed with respect to their structure-activity relationship. The greatest cell growth inhibitory effects display palladium dichloro adduct and acetate bridged dimmer, which may be regarded as having antitumor properties since their IC50 values are lower than 10 micromolar.

The synthesis, some spectroscopic properties and antitumor activity of new molecular and ionic platinum(II) complexes of diethyl ester of 8-quinolylmethylphosphonic acid (8-dqmp) have been reported. The new complexes were characterized on the basis of elemental and thermogravimetric analyses, magnetic and conductometric measurements, and by infrared and NMR spectral studies. As a preliminary assessment of their biological activity, complexes were evaluated for their in vitro antutumor activity in an epidermoid human (KB) and murine leukemia (L1210) tumor cell lines.

The synthesis, spectroscopic and biological properties of the novel palladium(II) complexes with monoethyl (HL1) and monobutyl (HL2) ester of [alpha-[(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 ring. The former are cyclopalladated chloro-bridged binuclear complexes in which the deprotonated ligand undergoes palladation at the azo nitrogen and the ortho-carbon, while the latter mononuclear complexes 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 infrared, 1H, 13C and 31P nuclear magnetic resonance and ESI-mass spectroscopic studies. The in vitro antitumor activity of all the complexes was evaluated against 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.

The synthesis, spectroscopic and biological properties of palladium(II) halide complexes of ethyl 8-quinolylmethylphosphonate have been reported. It was shown that depending on the acidity of the reaction medium, the molecular or the ionic complexes could be obtained. A detailed infrared, electronic, mass and nuclear magnetic resonance spectroscopic studies, accompanied by the thermal, magnetic and conductometric measurements, have been applied for identification and characterization of the novel complexes. The in vitro antitumor activity of complexes was evaluated against KB and L1210 cell lines as a preliminary screening for their biological activity, and the results obtained were compared with those obtained for the complexes of diethyl 8-quinolylmethylphosphonate (8-dqmp).

U okviru istraživanja novih biološki aktivnih paladij(II) kompleksa s derivatima različitih aminofosfonskih kiselina, prikazana su spektroskopska i biološka svojstva paladij(II) kompleksa s monoetil 8-kinolilmetifosfonatom (8-mqmp). Reakcijom PdX_4^2- i 8-mqmp.HX (X=Cl, Br) dobiveni su ionski kompleksi s protoniziranim ligandom kao kationom i tetrakloropaladijevim odnosno heksabromodipaladijevim kompleksom kao anionom. Reakcijom u alkalnom mediju dobije se neutralni monohidratni kompleks u kojemu 8-mqmp djeluje kao bidentatni ligand preko kinolinskog dušika i kisika fosfonske kiselinske skupine. Spektroskopska istraživanja (infracrveni i elektronski spektri te spektri nuklearne magnetske rezonancije), uz magnetska mjerenja i mjerenja molarne vodljivosti, primjenjena su za ispitivanje paladijevih kompleksa. Biološka svojstva kompleksa ispitana su određivanjem njihove in vitro antitumorske aktivnosti na stanicama karcinoma kože i limfnih žlijezda (KB i Molt4/C8 stanice) kod ljudi i leukemije kod miša (L1210 stanice).

Continuing our research on palladium complexes with organophosphorus chelate ligands, the synthesis as well as some spectroscopic and biological properties of the molecular and ionic palladium(II) complexes with the monoethyl 2-quinolylmethylphosphonate (2-mqmp) have been reported. Dihalogenopalladium complexes containing N-bonded monodentate ligand in a trans square-planar fashion were obtained by interaction of 2-mqmp with PdX_4^2- (X=Cl, Br) either in the methanolic or in the aqueous medium at pH~3.5. The neutral complex where 2-mqmp acts as a bidentate chelate ligand through the quinoline nitrogen and the phosphonic acid group was isolated at pH~6. From the HX acidic medium were isolated the ion-pair salt complexes containing the protonated quinoline ligand as cation and the trihalogenopalladium complex as anion. The in vitro cytostatic activity of all the complexes was evaluated against an epidermoid human carcinoma (KB) and against murine leukeamia (L1210) cell lines.

The new palladium(II) halide complexes with diethyl and dibutyl esters of [alpha-(4-benzeneazoanilino)-2-hydroxybenzyl]phosphonic acids have been prepared. All complexes have been characterized by elemental analysis, detailed spectroscopic studies (IR, UV-VIS and FAB-MS), thermogravimetric, magnetic and conductometric measurements. The effectiveness of all complexes as potential antitumor drugs have been tested in vitro on KB cell line derived from a human epidermoid carcinoma and on murine leukemia L1210 cell line.

The duration of cell proadhesive effects induced by imidazolium trans-imidazole dimethyl sulfoxide tetrachlororuthenate (NAMI-A), a compound endowed with in vivo antimetastatic properties, was tested in vitro on the human epithelial tumor cell line KB. The intensity of proadhesive effects continues to increase up to 48 to 72 h after NAMI-A withdrawal and declines only after 96 h. The proadhesive effect on cells seeded on fibronectin is greater than on plastic, since it already reaches its maximum after 24 h. This effect suggests a role for integrin activation, which is further stressed by the inhibitory activity of the disintegrin molecule echistatin. The intensity and duration of NAMI-A's proadhesive effects are correlated to cell exposure time and to the rapid release of NAMI-A metabolites in the culture medium in the first 5 min after drug withdrawal. These metabolites are probably neutral species with ruthenium-bound bioligands to allow for the rapid exchange between cells and extracellular medium. These data suggest a long-lasting effect of NAMI-A in biological systems, even at very low concentrations, and stress the low and reversible effects on kidney, where it naturally concentrates. These data on proadhesive effects are, further, relevant for in vivo antimetastatic effects, as this adhesion is associated to cell motility and invasion, which in turn are related to tumor malignancy and metastasis.

Imidazolium trans -imidazoledimethylsulphoxidetrachlororuthenate (NAMI-A) was tested in vitro on the pro-adhesive properties, evaluated as resistance to trypsin treatment, which is a bona fide measure of adhesion strength, of KB and HeLa carcinoma cell lines and on human polymorphonuclear neutrophils (HPMN). NAMI-A increased the pro-adhesive activity of KB cells at 0.001 mM concentration, after few minutes incubation and this effect was not influenced by the vehicle used for cell challenge, neither did it depend on NAMI-A concentration or on temperature. The same effect occurred on HeLa cells at 0.01 mM NAMI-A. This effect, detected at concentrations up to 100 times lower than those necessary to block cells at the G 2 -M premitotic phase of cell cycle, or to inhibit matrix metalloproteinase release or cell invasion, was not related to ruthenium uptake by tumour cells. HeLa cells and healthy HPMN, following short exposure to 0.1 mM NAMI-A, assumed a different shape, with the extrusion of filopodia (HeLa) and of large lamellopodia (HPMN), which increased their interactions with the substrate. This effect was attributed to stabilisation, altered turnover and sensitivity to cytochalasin D of actin filaments. Provided that adhesion is associated with cell motility and invasion, these data suggest that NAMI-A may exert antimetastatic properties at concentrations lower than those observed in the lungs at the end of a conventional intraperitoneal treatment in vivo.

3,5-Dimethyl-1-(2′-pyridyl)pyrazole (DMPP) reacts with SnX4 and R2SnX2 (XCl, Br, I; R=Me, Et, Bu, Ph) to yield adducts of types [SnX4(DMPP)] and [SnR2X2(DMPP)], respectively. The structure of [SnEt2Br2(DMPP)] has been determined by X-ray diffractometry. The crystal consists of discrete [SnEt2Br2(DMPP)] molecules with the metal atom octahedrally coordinated to two Br atoms [SnBr=2.631(3), 2.703(3) A; BrSnBr=98.00(10)°], two ethyl carbons [SnC=2.11(3), 2.143(19) A; CSnC=172.3(11)°] and the two donor N atoms of the ligand [SnN=2.379(16), 2.387(16) A; NSnN=66.8(6)°]. The IR data and Mossbauer parameters are consistent with all the organotin derivatives having, similar geometry whereas in the case of the [SnX4(DMPP)] complexes the results of both techniques support the expectation of cis stereochemistry. The 1H NMR data indicate significant dissociation in solution. The chlorobutyl derivative exhibited significant in vitro antitumour activity against the human carcinoma cell line KB.

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.

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.

Spectroscopic ( 1 H 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) 2 X 2 , chelate Pd(2-mqmp) 2 · 2H 2 O and ion-pair salt complexes [2-H 2 mqmp] + [Pd(2-Hmqmp)X 3 ] − (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.

Complexes of copper(I) and copper(II) with 1,1′-bis(diphenylphosphino)ferrocene and with 1,1′-bis(oxodiphenylphosphoranyl)-ferrocene are found to exhibit cytostatic potency towards Eagle's KB cell line.