Search

Complexes of the general structure cis-[PtX(2)(hydrazide)(2)] and cis-[PtX(2)NH(3)(hydrazide)], where X=Cl(-), Br(-) and I(-), and hydrazide=cyclohexylcarboxylic acid hydrazide (chcah), cyclopentylcarboxylic acid hydrazide (cpcah), 3-aminocyclohexanspiro-5-hydantoin (achsh) and 3-aminocyclopentanspiro-5-hydantoin (acpsh), were investigated with respect to aqueous stability, DNA platination rates and cytotoxic activity on a panel of seven human cancer cell lines as well as a cisplatin-resistant cell line. Stabilities in aqueous solution, determined by RP-HPLC and UV-Vis methods, were highly dependent on the type of halide ligand, with stability decreasing in the order I(-)Cl(-)Br(-). Added chloride (100 mM) only stabilized the dichloro-Pt(II) complexes containing the hydrazide as part of a hydantoin ring (i.e., achsh). Platination of calf thymus DNA determined by AAS was most rapid with dichloro-Pt(II) complexes containing achsh ligand. The mixed-amine dichloro-Pt(II) complexes with either chcah or cpcah ligands also platinated DNA80%, but at a slower rate, while dihydrazide dichloro-Pt(II) complexes with either chcah or cpcah ligands resulted in25% DNA platination at 24 h. cis-[PtX(2)(hydrazide)(2)], where hydrazide=chcah or cpcah, were the most potent compounds (chcahcpcah), but activity was independent of the halide ligand (I(-)=Cl(-)=Br(-)). These complexes showed no cross-resistance with cisplatin, but they also showed little differentiation in potency over the seven cell lines. Complexes with the hydantoin ligands achsh and acpsh were inactive in all cell lines. Thus, neither stability in aqueous media nor covalent binding to DNA are correlated with biological activity, suggesting that cis-dihydrazide Pt(II) complexes act by a unique mechanism of action.

Four new platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin (acpsh) and 3-aminocycloheptanespiro-5-hydantoin (achpsh) were synthesized and characterized by elemental analysis, IR and 1NMR spectra. The spectral analyses indicated a cis-square planar structure of the complexes with ligands coordinated via the NH2 group. The complexes were evaluated for in vitro cytotoxicity in murine erythroleukemia (MEL) cells, clone F4N, using cell-growth and macromolecular synthesis assay. The compounds, with exception of [Pt(NH3)(achpsh)Cl2] (IV), exhibited much lower cytotoxicity than that of cisplatin (DDP). Compound IV was nearly as cytotoxic as DDP. The new complexes exerted low antibacterial activity as assessed by seven bacterial strains

The induction of HSP90 in murine erythroleukemia cells, clone F4 N, by cisplatin (DDP) was examined using indirect immunofluorescence and avidin-biotin technique, and compared with cisplatin cytotoxicity. A reverse dependence of HSP90 induction time was found on a wide range of cisplatin concentrations (0.5D10 μᴍ), which proved to be cytostatic up to 48 h of continuous treatment. Thus, the observed induction pattern of HSP90 in F4 N cells strictly correlated with their high tolerance toward DDP. This indicates that HSP90 might be responsible, at least in part, for cisplatin resistance of F4 N cells

The combination of cis-diamminedichloroplatinum (II) (DDP, cisplatin) and topoisomerase II inhibitor teniposide (VM-26) has been shown to exert a synergistic effect in the clinical treatment of cancer. In this study, the combined effect of DDP and VM-26 on the growth and induction of apoptosis in synchronized murine erythroleukemia (MEL) cells, treated at the beginning or in the middle of S-phase of cell cycle, was examined. MEL cells, clone F4 N, were synchronized by a double thymidine block leading to accumulation of 70% of cells at the G1/S boundary. The growth-inhibitory effect of DDP and VM-26 applied alone were stronger in the middle of the S-phase than at the beginning. Morphological analysis showed that the majority of the cells revealed typical signs of apoptosis: nuclei fragmentation and appearance of apoptotic bodies. The combination of both agents at low concentrations had a synergistic effect on cytotoxicity. At higher concentrations the effect was additive. The remainder of the cells were characterized by unbalanced growth, aberrant mitosis and appearance of multinucleated cells. These processes led to delayed cell death. The appearance of aberrant mitosis was more expressed after treatment in the middle of the S-phase. It is likely that as a result of the combined action of cisplatin and VM-26, cells become supersensitive to the ability of topoisomerase II inhibitor to influence mitosis, and this increased sensitivity may contribute to the observed synergism.

New platinum(II) complexes of cyclohexanecarboxylic acid hydrazide (chcah) were synthesized and characterized by elemental analysis, IR. and 1H NMR spectra. Their inhibitory effects on cell growth and macromolecular synthesis of Friend leukemia cells in culture as well as the in vivo antitumor activity towards L1210 leukemia in mice were compared with those of complexes containing differently substituted aromatic acid hydrazides. Some of the complexes exhibited antineoplastic activity. No correlation between the in vitro cytotoxicity and the in vivo antitumor activity was found. However, there was a relationship between the in vitro macromolecular synthesis inhibition profile and the in vivo antineoplastic effect, similar to that of cisplatin. On the other hand, only agents containing one ammine ligand were active in vivo. The substitution of the aromatic ring by a cycloalkane residue increased significantly the antitumor effect, with [Pt(NH3)(chcah)Cl2] being the most active compound in this study.

In the title compound, cis-ammine(benzohydrazide-N')dichloroplatinum(II), cis-[PtCl 2 (C 7 H 8 N 2 O)(NH 3 )], the benzoylhydrazine ligand is bonded to the Pt atom through its amino group. The Pt-Cl and Pt-N distances are in the ranges 2.293 (5)-2.318 (5) and 2.01 (1)-2.08 (1) A, respectively. The arrangement of molecules in the monoclinic unit cell approximates P2 1 /c space-group patterns; however, the true spacegroup symmetry is P2 1 . The two crystallographically independent molecules have significantly different conformations about the Pt-N(hydrazine) bond. The structure is held together by a complicated network of N-H...O and N-H...Cl hydrogen bonds

The complexes [Pt(bah)2X2], [Pt(NH3)(bah)Cl2].0.5H2O, [Pt(mbah)2X2], and [Pt(NH3)(mbah)Cl2] (bah = benzoic acid hydrazide, mbah = 3-methoxybenzoic acid hydrazide; X = Cl, Br, I) have been prepared and characterized by elemental analysis, electric conductivity, IR, 1H NMR, and electronic spectra. A cis-square planar structure with hydrazide ligands coordinated via the NH2-groups has been proposed for these complexes. The complexes have shown a growth-inhibitory effect against Friend leukemia cells in culture comparable to that of the antitumor drug cisplatin.

The present work investigates the effect of cis-DDP (DDP, diamminedichloroplatinum(II)), trans-DDP, SPC (spermine platinum(II) complex), and K2PtCl4 on the activity of the CTP synthetase in the cytosol of Ehrlich ascites tumor cells. To study their in vitro effect, the platinum compounds were supplemented to the incubation mixture for the enzyme assay. A concentration dependent inhibition of the CTP synthetase was found which was strongest in the case of trans-DDP. When ascites cells collected from mice, pretreated in vivo with platinum compounds, were used, the enzyme assay showed that the inhibition is strongest in the case of cis-DDP and K2PtCl4 (about 90% inhibition). This distinct inhibitory effect of the platinum compounds in the present experiments may be explained with the metabolic conversions of the compounds in the organism to their more active forms and/or with the inhibition of the protein biosynthesis under their influence because the lifetime of the CTP synthetase is short. This last assertion is proved in this work by control experiments with the antibiotic cycloheximide, which is an inhibitor of the protein biosynthesis.

The complexes CrL3Cl3.2H2O (I), CoL3Cl2.3H2O (2), CoL3Br2.H2O (3), NiL3Cl2.3H2O (4) and CuLCl2 (5), where L is (dimethylphosphinyl)methanamine, were synthesized and characterized by infrared and electronic spectra. The X-ray single crystal analysis of 4 (trigonal, space group R 3c, a = 11.340(2), c = 63.708(8) A, V = 7095(2) A, Z = 12) revealed a structure containing tris-chelated fac[NiL3]2 + cations in which L is coordinated via the amino nitrogen and phosphoryl oxygen atoms. The statistically disordered chloride ions and water molecules occupy voids between the cations. On the basis of spectral data, 1,2 and 3 are formulated as consisting of pseudo-octahedral tris-chelate cations [ML3]n + (n = 2 or 3) and non-coordinated halide ions and water molecules. A polymeric structure in which Cu(II) is surrounded by four bridging chlorides and two bridging L ligands is ascribed to 5.

The antitumor activity of cis-platin is believed to result from its interaction with cellular DNA and subsequent processing of DNA adducts by damage recognition proteins. Among them are the high mobility group (HMG) proteins 1 and 2, which have been hypothesized to mediate the effect of cis-platin. One possibility suggests that the tight binding of HMG1 to DNA adducts blocks the repair of damaged DNA. In order to further evaluate such a mechanism, several cis-platinum complexes with known antitumor activity have been used to treat DNA and the affinity of HMG1 to the DNA adduct induced by each drug was determined. The dissociation constants for the complexes of HMG1 with the platinated probe were obtained by gel mobility shift assays. The antitumor activity of the tested platinum compounds was found to correlate with the binding affinity of HMG1 to the respective drug-DNA adduct. These findings support the view that HMG1 contributes to cytotoxicity of cis-platin by shielding damaged DNA from repair. In addition, they offer a fast test for screening new platinum compounds for antitumor activity.

New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cissquare planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10–20 μM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.

Cis-diamminedichloroplatinum(II) (cis-DDP) is known as an effective anticancer drug. Its therapeutic effect is supposed to be a consequence of the covalent binding to DNA. A number of cellular proteins were found to bind selectively to DNA modified by cis-DDP (but not by its isomer frans-DDP). Here we present our observations on interaction of the linker histone H1 with cis- and trans-DDP modified DNA fragments. The results afford new experimental information about the preferential binding of histone H1 to cis-DDP-distorted DNAs versus trans-DDP modified ones.

The complexes [Pt(NH3)(pmbah)Cl2], [Pt(NH3)(pcbah)Cl2], [Pt(pmbah)2X2] and [Pt(pcbah)2X2] (pmbah = 4-methoxybenzoic acid hydrazide, pcbah = 4-chlorobenzoic acid hydrazide; X = Cl, Br, I) have been synthesized and characterized by elemental analysis, electric conductivity, 1H NMR, IR, and electronic spectra. A cis-square planar structure with hydrazide ligands coordinated via the NH2 groups has been proposed for these compounds. The complexes, but not the free ligands, have shown a strong growth inhibitory effect in Friend leukemia cells in vitro, most of which are more active than cisplatin.

The complexes [Pt(dapo) 2 Cl 2 ], [PtNH 3 (dapo)Cl 2 ], [Pt(py)(dapo)Cl 2 ], [Pt(mbpo)Cl 2 ]·H 2 O, [Pt(mbpo)(OH) 2 Cl 2 ]·H 2 O, [Pd(dapo) 2 Cl 2 ], and [Pd(mbpo)Cl 2 ], where dapo is dimethyl aminomethylphosphine oxide and mbpo is methyl bis(aminomethyl)phosphite oxide have been synthesized and characterized by elemental analyses, electric conductivity, infrared, 1 H NMR and electronic spectra. The ligands are found to be coordinated only via the amino groups. The complexes are of cis-square planar configuration with the exception of [Pt(mbpo)(OH) 2 Cl 2 ] ·H 2 O which is pseudo-octahedral. An in vivo antitumor screening of the complexes against Leukemia L 1210 was performed. A considerable activity (T/C = 233%) was observed for [PtNH 3 (dapo)Cl 2 ]. The activity of the remaining complexes was below the accepted criterion.

The pyruvic acid thiosemicarbazone was found to inhibitin vitro the soluble ornithine carbamoyl transferase as well as the enzyme in a mitochondria-rich cell fraction. For proving the inhibition of ornithine carbamoyl transferase in mitochondria-rich fraction a new method for DEAE-thin-layer chromatography of radiocarbon labelled citrulline and ornithine was used. The mitochondria prepared by discontinuous sucrose density gradient centrifugation are physiologically active and oxidized succinate under state 3 conditions. The respiratory control ratio was determined to 3.3. The results obtained show that this analogue of pyruvic acid is an inhibitor of ornithine carbamoyl transferase.

The antibacterial activity of 2-thiouracil, 2-methylthiouracil, 2-hydrazinouracil, 2,4-dithiouracil, 2-thio-4-hydrazinouracil, 2-thio-6-azathymine, 2-hydrazino-6-azathymine, 2,4-dithio-6-azathymine, 2-thio-4-hydrazino-6-azathymine, 2,4-dimethylthio-6-azathymine, 2-methylthio-4-hydrazino-6-azathymine, 4-thio-6-azauracil and 4-hydrazino-6-azauracil has been studied on the growth of: Staphylococcus aureus 209, Streptococcus faecalis 775, Escherichiia coli 387, Pseudomonas aeruginosa, Bacillus subtilis, Candida tropicalis and Neurospora crassa 9863. The highest inhibitory effect was observed with 4-hydrazino-derivatives of 2-thiouracil, 6-azauracil and 2-thio-6-azathymine.

A platinum(II) complex with an electroneutral adduct of stannous chloride [Pt(Sn(DPPO)Cl2)2Cl2] (DPPO = dimethyl phthalimidomethylphosphine oxide) is synthesized and characterized by infrared and electronic spectra.