Water-soluble Platinum Research Articles

Synthesis and antitumor activity of water-soluble 2-benzyl-1,2-diaminobutane-α-oxycarboxylatoplatinum(II) complexes

Nine new water-soluble platinum(II) complexes were synthesized and characterized. Racemic (±)-2-benzyl-1,2- diaminobutane or the corresponding enantiomers (+)-2-benzyl-1,2-diaminobutane and (−)-2-benzyl-1,2-diaminobutane were used as nitrogen chelate ligands. The chloride leaving groups of the resulting N,N′-2-benzyl- 1,2-diaminobutanedichloroplatinum(II) complexes were replaced by the anions of four α-hydroxycarboxylic acids to increase the water solubility. As α-hydroxycarboxylic acids, lactic acid, glycolic acid, mandelic acid and α- hydroxyisobutyric acid were used. For N,N′-2-benzyl-1,2-diaminobutane- O,O′-lactatoplatinum(II), the different geometrical and optical isomers were separated. The antitumor activity of the platinum(II) complexes was examined in vitro towards the MDA-MB 231 breast cancer cell line and in vivo towards the P 388 leukemia of the CD 2F 1 mouse. Contrary to the insoluble dichloro complexes, the α-oxycarboxylatoplatinum(II) complexes exhibited good water solubility associated with a high antitumor activity.

(1,2-Diaryl-1,2-ethylenediamine)platinum(II) complexes with sulfato and 3-sulfopropionato leaving groups: investigations with different types of coordination in the solid state, in solution and reactions with nucleophiles

The syntheses, solid state and solution chemistry, and the in vitro cytotoxic activities of water soluble (1,2-diaryl-1,2-ethylenediamine)platinum(II) complexes, having either the sulfato or the novel sulfopropionato anionic leaving group, are described. The compounds were prepared by allowing the (1,2-diaryl-1,2-ethylenediamine)diiodoplatinum(II) complexes and either silver sulfate or silver sulfopropionate to react in water. IR studies of the complexes in the solid state indicate that the preparations are mixtures of platinum species, whereby the anionic leaving groups show varying forms of platinum coordination. These compositions vary depending on the procedure used to isolate the platinum complexes. The aqueous solution chemistry was investigated by means of a reversed-phase HPLC assay. The results of these studies show the presence of several platinum species in solution. Based on the column retention properties of the species as well as their behavior to changes in pH, it is concluded that these solution components are various monomers and oligomers of the parent platinum complex. These results are in agreement with previous 195Pt and 15N NMR studies from other diamineplatinum(II) complexes. The type of aromatic substitution has an influence on the qualitative composition of the aqueous platinum species; an additional platinum species is observed in aqueous solutions of platinum complexes possessing an ortho phenol group compared to the complexes possessing a para fluorine group. Aqueous reactions of the platinum complexes with chloride indicate that the sulfopropionato ligand is more stable-bound than the sulfato ligand, however, results from cell culture cytotoxicity tests show little difference between the cytotoxic activities of the complexes possessing a sulfato or a sulfopropionato leaving group.

Determination of platinum emissions from a three-way catalyst-equipped gasoline engine

Platinum emissions from two automotive monolithic catalysts have been determined under laboratory conditions on a computer controlled dynamometer. Three stationary speed simulations and the U.S.-75 cycle were applied. Particles were classified on a Berner Impactor and analysed by atomic absorption spectrometry using a signal addition technique. Condensates were also sampled to determine volatile compounds. For quality control, several matrix element studies were performed to demonstrate the accuracy of the analytical method. The emission concentrations, as determined in several test runs and repetitive sampling, range from 3 to 40 ng m−3. In contrast to published data from pellet oxidation catalysts, the emission concentrations determined are lower by 2 orders of magnitude. A possible volatile or watersoluble platinum fraction is most probably negligible.

Cis-Diaminedichloroplatinum(II) complexes reversibly bound to water-soluble polyaspartamide carriers for chemotherapeutic applications. I. Platinum coordination to preformed, carrier-attached ethylenediamine ligands

Copolyaspartamides3–5, bearing the ethylenediamine (en) ligand as a repetitive side-chain component in addition to various hydrosolubilizing groups, are synthesized from polysuccinimide1 by a two-step aminolytic ring opening reaction. The completely water-soluble polyamides, possessing inherent viscosities of 5–20 ml g−1, are used as polymeric carriers for the “anchoring” of the biomedically important diaminedichloroplatinum(II) coordination complex. Conjugate formation is brought about by treatment of the carriers with the tetrachloroplatinate(II) dianion in aqueous solution at pH 6.0 ± 0.5. The resulting, water-soluble conjugates3-Pt-5-Pt, purified by dialysis (12,000–14,000 molecular mass cutoff) and isolated in the solid state by freeze-drying from aqueous solution, possess platinum contents in the typical range of 15–25%. The metal is bound as acis-dichloro-en-Pt(II) complex to the polymer main chain via a short spacer segment incorporating a biofissionable amide link suitable forin vivo release of the complex. The conjugates are of interest as water-soluble macromolecular platinum coordination compounds for potential use in the chemotherapy of cancerous diseases.

Synthesis and Characterization of a Series of Water Soluble Amidomalonato-(lR,2R-Cyclohexanediamine)Platinum(II) Complexes

Abstract A new series of water soluble platinum(II) complexes of the type [Pt(DACH)[R-CH(COO)2]], wherein DACH represents IR,2R-cyclohexanediamine and R represents formamido. acetamido, (penta-O-acctyl-gluconyl)amino, and gluconylamino have been synthesized. The modes of binding of amidodicarboxylic acid derivatives in these complexes have been determined by various spectroscopic techniques: 1H, 13 C, and 195PtNMR; 2D-COSY{1H-1H} and 2D-HETCOSY{1H-13C} NMR, MS(FAB), IR and conductivity measurements.

A rapid method for the synthesis of water-soluble platinum(II) amine and pyridine complexes

Seventeen cis-[Pt(am)2(ONO2)2] complexes (am = methylamine, cycloalkylamines, substituted pyridines, aniline, or benzylamine; 2am = 2,2′-bipyridyl) were synthesized by reaction of cis-[Pt(am)2l2] with silver nitrate in acetone. The reaction was rapid (5–20 min at room temperature) with a yield of about 85%. The complexes appear to be stable in acetone with respect to isomerization. Thus, after 1 h at 25 °C acetone solutions of cis-[Pt(am)2X2](am = cyclohexylamine or 4-methylpyridine; X = I or ONO2) showed no isomerization judging by 1H n.m.r. spectroscopy of these compounds and their corresponding trans isomers.

A new family of water-soluble, third generation antitumor platinum complexes.

[1,1-Cyclobutanedicarboxylato(2)-O,O'](1,3-dioxane-5,5-dimethan amine- N,N')platinum(II), 3a, a third generation, very water-soluble platinum complex, has been synthesized along with several of its analogues. All members of the new family contain a 1,3-dioxane or 1,3-dioxolane-1,3-diamine as their basic ligand, a moiety which contributes to their increased water solubility, and a bidentate acid ligand, which is responsible for their good stability. They were all easily crystallized and characterized by 1H NMR and elemental analysis, and the parent complex 3a was further characterized by 13C NMR. Their very desirable physical properties combined with their broad spectrum of antitumor activity and reduced toxicity make them good candidates of further development.

Antitumor activity of a new platinum complex, oxalato ( trans-l-1,2-diaminocyclohexane)platinum (II): new experimental data

Antitumor activity of a new platinum complex, oxalato ( trans- l-1,2-diaminocyclohexane) platinum (II) ( l-OHP), was studied. This water-soluble platinum complex showed a more prominent life-prolonging effect on a mouse leukemia L1210 than cisplatin (DDP). By an intermittent treatment schedule cured mice were observed at the optimal dose. In addition, a subline of L1210 having a 40-fold resistance to DDP (L1210/DDP) showed lack of cross-resistance to l-OHP both in vivo and in vitro. Especially in vivo l-OHP was more active against L1210/DDP than against the original L1210, and all mice were cured at doses of 6.25 and 3.12 mg kg . l-OHP was also effective against several mouse tumors such as P388 leukemia, B16 melanoma, Lewis lung carcinoma, colon 26 and colon 38 adenocarcinomas, and M5076 fibrosarcoma, though its antitumor spectrum was somewhat different from that of DDP. The synthesis of both DNA and RNA in L1210 cells was inhibited by about 50 % with exposure to 10 μM of l-OHP for 1h, followed by postincubation in drag-free medium for 6–24 h, while only the inhibition of DNA synthesis was observed by DDP in the same experiment. If severe toxicity is not observed in preclinical study, l-OHP expected to be a new clinically active Pt complex.

Bildung wasserlöslicher Histidin-Platin- Komplexe aus metallischem Platin und Histidin / Formation of Water Soluble Histidine Platinum Complexes from Metallic Platinum and Histidine

Abstract Metallic Platinum dissolves under oxygen atmosphere in aqueous histidine solution. About 0.1 to 0.3 μmol of a water soluble histidine platinum complex per ml solution have been found by atomic absorption spectroscopy.

A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyliminodiacetato-diaminocyclohexane platinum (II)

A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.

Structure-antitumor activity relationship for new analogs of thecis-dichloro(l,2-diamino cyclohexane) platinum(II) complex

In 1977, Gale and associates reported the synthesis and antitumor activity of a series of Pt(II) complexes containing 1,2-diaminocyclohexane as the ligand. Certain of these complexes showed superior activity and greater water solubility compared to cis-Pt(NH3)2Cl2 complexes ("Neoplatin"). In this paper we report the synthesis and antitumor activity of some 40 new water soluble platinum(II) and platinum(IV) complexes. The following classes of the cis-Pt(L)Cl2 complexes were obtained, where L = 1,2-diaminocyclohexane: (a) cis-Pt(L)(X), where X is a derivative of homophthalic acid or a derivative of 1,3-benzendicarboxylic acid, (b) cis-Pt(L)(X)(OH)2 and cis-Pt(L)(X)(Cl)2 complexes, where L and X are the above-mentioned ligands, (c) cis-Pt(L)(X)2 complexes where X is the monoanion of an organic xanthate or dithiocarbamate and L = 1,2-diaminocyclohexane, (d) their corresponding Pt(IV) analogues, Pt(L)(X)2(OH)2 and Pt(L)(X)2(Cl)2. All complexes were assayed against P388 tumors and/or KB cell-bearing mice. The observed antitumor activities were correlated with the structures and spectra of the complexes as well as with the results of EHMO calculations performed on the leaving ligand molecules. A number of the most active complexes were also tested for activity against ADJ/PC6 Yoshida and S-180 tumors in vivo.

Antitumor activity of water-soluble platinum(II) complexes of 1,2-cyclohexanediamine isomers.

Dichloroplatinum(II) complexes of 1,2-cyclohexanediamine isomers were reported to have high antitumor activity against leukemia L-1210 and P-388, but they were hardly soluble in water and, therefore, dibromo- and diiodo-platinum(II) complexes of 1,2-cyclohexanediamine isomers were prepared. They were not soluble in water but showed high antitumor activity. When the chloride ions are replaced with sulfate ions, they become soluble and also they are anti-tumor active. Bismonobromoacetatoplatinum (II) complexes were synthesized and tested. Mono- and bis-(D-glucuronato)platinum(II) complexes of 1,2-cyclohexanediamine isomers were newly synthesized. All of them were freely soluble in water and showed high antitumor activity with low toxicity. The chelated mono(D-glucuronato)platinum(II) was found to be more effective than the monodentate bis(D-glucuronato)platinum (II) complexes.

Formation and catalytic properties of water-soluble phosphine complexes

Using sulfonated triphenylphosphine, a number of water-soluble platinum metal — phosphine complexes were prepared. Some of them show a pronounced reactivity towards small molecules and the ruthenium compound catalyzes the hydrogenation of ketocarboxylic acids.