Silver(I) complexes containing antifungal azoles: significant improvement of the anti-Candida potential of the azole drug after its coordination to the silver(I) ion.

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 µM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.

Metal complexes with valuable biomolecules produced by Pseudomonas aeruginosa: a review of the coordination properties of pyocyanin, pyochelin and pyoverdines.

Pseudomonas aeruginosa is an opportunistic, Gram-negative bacterium, involved in severe infections associated with cystic fibrosis, pneumonia, burn wounds, ocular diseases, and immunosuppressive illnesses, and is a major cause of intrahospital infections. This bacterium is also one of the most commercially and biotechnologically significant microorganisms, since it can produce valuable biomolecules which represent a rich source of potential drug candidates. On the other hand, metal complexes have been used in medicine for both therapeutic and diagnostic purposes since ancient times. This class of compounds can adopt different geometries and generally have a three-dimensional shape, contributing to their higher clinical success compared to flat purely organic compounds. In the present review article, attention has been devoted to the three natural products derived from P. aeruginosa, namely pyocyanin, pyochelin, and pyoverdine(s) and their ability to form complexes with different metal ions, including iron(II/III), manganese(II/III), gallium(III), chromium(III), nickel(II), copper(II), zinc(II) and cadmium(II). Investigation of the coordination properties of pyocyanin, pyochelin, and pyoverdine(s) towards these metal ions is important because the resulting bacterially derived natural product-metal complex can serve as a model for the study of metal ion metabolism (transport and storage) in living systems and might also be considered as a novel therapeutic agent for potential use in medicine.

Dinuclear platinum(II) complexes as the pattern for phosphate backbone binding: a new perspective for recognition of binding modes to DNA.

The mechanism of action of most approved drugs in use today is based on their binding to specific proteins or DNA. One of the achievements of this research is a new perspective for recognition of binding modes to DNA by monitoring of changes in measured and stoichiometric values of absorbance at 260 nm. UV-Vis and IR spectroscopy, gel electrophoresis and docking study were used for investigation of binding properties of three dinuclear platinum(II) complexes containing different pyridine-based bridging ligands, [{Pt(en)Cl}2(µ-4,4'-bipy)]Cl2·2H2O (Pt1), [{Pt(en)Cl}2(µ-bpa)]Cl2·4H2O (Pt2) and [{Pt(en)Cl}2(µ-bpe)]Cl2·4H2O (Pt3) to DNA (4,4'-bipy, bpa and bpe are 4,4'-bipyridine, 1,2-bis(4-pyridyl)ethane and 1,2-bis(4-pyridyl)ethene, respectively). In contrast to the system with well-known intercalated ligand (EtBr), covalently bound ligand (cis-Pt) and with minor groove binder (Hoechst 33258), which do not have significant differences in measured and stoichiometric values, the most pronounced deviations are recorded for two dinuclear platinum(II) complexes (Pt1 and Pt2), as a consequence of complex binding to the phosphate backbone and bending of DNA helix. The hydrolysis of complexes and changes in DNA conformation were also analysed as phenomena that may have an impact on the changes in absorbance.

In vitro cytotoxic activities, DNA- and BSA-binding studies of dinuclear palladium(II) complexes with different pyridine-based bridging ligands.

Three new dinuclear palladium(II) complexes with general formula [{Pd(en)Cl}2(µ-L)]2+ (L is pyridine-based bridging ligand 4,4'-bipyridine (4,4'-bipy, 1), 1,2-bis(4-pyridyl)ethane (bpa, 2), 1,2-bis(4-pyridyl)ethylene (bpe, 3) and en is bidentate coordinated ethylenediamine) were synthesized and characterized by elemental microanalyses, NMR (1H and 13C), IR and UV-Vis spectroscopy. In vitro cytotoxic activity of these complexes against human A549 and murine LLC1 lung cancer cells, as well as two human HCT116 and SW480 and one murine CT26 colon cancer cells was investigated using MTT assay (MTT is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). The potential of complexes 1-3 to induce apoptosis was tested by flow cytometric analysis of Annexin V and propidium iodide stained treated cells, while their antiproliferative activity was analyzed by detection of Ki67 expression in treated cancer cells. The DNA binding affinity of complexes 1-3 was evaluated by UV-Vis, fluorescence emission spectroscopy and by viscosity measurements in aqueous phosphate buffer solution at pH 7.40. Furthermore, interaction of these complexes with bovine serum albumin was investigated by fluorescence spectrometry. The present study showed that the nature of pyridine-based bridging ligand (L) in dinuclear [{Pd(en)Cl}2(µ-L)]2+ complex has an influence on the complex preference for the cytotoxic activity and CT-DNA/BSA (CT-DNA is calf thymus DNA and BSA is bovine serum albumin) binding affinity.

Zinc(II) complexes with aromatic nitrogen-containing heterocycles as antifungal agents: Synergistic activity with clinically used drug nystatin.

Three novel Zn(II) complexes, [ZnCl2(qz)2] (1), [ZnCl2(1,5-naph)]n (2) and [ZnCl2(4,7-phen)2] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV-Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1-3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.

New dinuclear palladium(II) complexes with benzodiazines as bridging ligands: interactions with CT-DNA and BSA, and cytotoxic activity.

Three new dinuclear Pd(II) complexes with general formula [{Pd(en)Cl}2(µ-L)](NO3)2 [L is bridging ligand quinoxaline (Pd1), quinazoline (Pd2) and phthalazine (Pd3)] were synthesized and characterized by elemental microanalyses, UV-Vis, IR and NMR (1H and 13C) spectroscopy. The interaction of dinuclear Pd1-Pd3 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV-Vis and fluorescence emission spectroscopy in aqueous phosphate buffer solution (PBS) at pH 7.40 and 37 °C. In addition, these experimental conditions have been applied to investigate the binding affinities of Pd1-Pd3 complexes to the bovine serum albumin (BSA) by fluorescence emission spectroscopy. In vitro antiproliferative and apoptotic activities of the dinuclear Pd(II) complexes have been tested on colorectal and lung cancer cell lines. All tested Pd(II) complexes had lower cytotoxic effect than cisplatin against colorectal cancer cells, but also had similar or even higher cytotoxicity than cisplatin against lung cancer cells. All complexes induced apoptosis of colorectal and lung cancer cells, while the highest antiproliferative effect exerted Pd2 complex.

Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure.

The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}2(µ-1,5-nphe)](ClO4)2 (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (±)-1,2-propylenediamine (Pt3), trans-(±)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes.

Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib.

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-κN7)] (1) and [AuCl3(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89µM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128µM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

Mononuclear gold(iii) complexes with l-histidine-containing dipeptides: tuning the structural and biological properties by variation of the N-terminal amino acid and counter anion.

Gold(iii) complexes with different l-histidine-containing dipeptides, [Au(Gly-l-His-NA,NP,N3)Cl]Cl·3H2O (1a), [Au(Gly-l-His-NA,NP,N3)Cl]NO3·1.25H2O (1b), [Au(l-Ala-l-His-NA,NP,N3)Cl][AuCl4]·H2O (2a), [Au(l-Ala-l-His-NA,NP,N3)Cl]NO3·2.5H2O (2b), [Au(l-Val-l-His-NA,NP,N3)Cl]Cl·2H2O (3), [Au(l-Leu-l-His-NA,NP,N3)Cl]Cl (4a) and [Au(l-Leu-l-His-NA,NP,N3)Cl][AuCl4]·H2O (4b), have been synthesized and structurally characterized by spectroscopic (1H NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. The antimicrobial efficiency of these gold(iii) complexes, along with K[AuCl4] and the corresponding dipeptides, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi, displaying their moderate inhibiting activity. Moreover, the cytotoxic properties of the investigated complexes were assessed against the normal human lung fibroblast cell line (MRC5) and two human cancer, cervix (HeLa) and lung (A549) cell lines. None of the complexes exerted significant cytotoxic activity; nevertheless complexes that did show selectivity in terms of cancer vs. normal cell lines (2a/b and 4a/b) have been evaluated using zebrafish (Danio rerio) embryos for toxicity and antiangiogenic potential. Although the gold(iii) complexes achieved an antiangiogenic effect comparable to the known angiogenic inhibitors auranofin and sunitinib malate at 30-fold higher concentrations, they had no cardiovascular side effects, which commonly accompany auranofin and sunitinib malate treatment. Finally, binding of the gold(iii) complexes to the active sites of both human and bacterial (Escherichia coli) thioredoxin reductases (TrxRs) was demonstrated by conducting a molecular docking study, suggesting that the mechanism of biological action of these complexes can be associated with their interaction with the TrxR active site.

Reactions of Dinuclear Platinum(II) Complexes with Peptides.

The present review article highlights recent findings in the reactions between different dinuclear Pt(II) complexes with peptides containing cysteine, methionine and histidine residues. The reactions of {trans-[Pt(NH3)2Cl]2(µ-X)}(2+) and {trans-[Pt(NH3)2(H2O)]2(µ-X)}(4+) type complexes with different bridging ligands (X) (X = pyrazine, 4,4'-bipyridyl and 1,2-bis(4-pyridyl)ethane) with the tripeptide glutathione proceeded in two steps. In the first step, one water or chlorido ligand of the dinuclear Pt(II) complex was substituted by the sulfhydryl group of GSH, while in the second step, the remaining water or chlorido ligand from the dinuclear Pt(II)-peptide complex was replaced by the second molecule of glutathione, finally leading to the formation of the {trans-[Pt(NH3)2(GS)]2(µ-X)}(2+) complex. It was shown that the bridging ligand had an important influence on the reactivity of these complexes with glutathione. No hydrolytic cleavage of any amide bond was observed in the reactions between these complexes and glutathione. However, in reactions performed in acidic media (2.0 < pH < 2.5) between dinuclear Pt(II) complexes with the general formulae {[Pt(L)(H2O)]2(µ-diazine)}(4+) (L is different bidentate coordinated diamine ligands and diazine is a pyrazine- or pyridazine-bridging ligand) and Nacetylated peptides containing L-methionine and L-histidine amino acids in the side chains (Ac-L-Met-Gly, Ac-L-His-Gly and Ac-L-Met-Gly-L-His-GlyNH2), regioselective cleavage of these peptides occurred. The mechanism of these hydrolytic reactions was discussed in relation to the structure of the diazine-bridged Pt(II) complex and the investigated peptides. A systematic summary of these results could contribute to the future design of new dinuclear Pt(II) complexes as potential reagents for regioselective cleavage of peptides and proteins.

Synthesis and evaluation of series of diazine-bridged dinuclear platinum(II) complexes through in vitro toxicity and molecular modeling: correlation between structure and activity of Pt(II) complexes.

Polynuclear Pt(II) complexes are a novel class of promising anticancer agents with potential clinical significance. A series of pyrazine (pz) bridged dinuclear Pt(II) complexes with general formulas {[Pt(L)Cl]2(µ-pz)}(2+) (L, ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd) and one pyridazine (pydz) bridged {[Pt(en)Cl]2(µ-pydz)}(2+) complex were prepared. The anticancer potential of these complexes were determined through in vitro cytotoxicity assay in human fibroblasts (MRC5) and two carcinoma cell lines (A375 and HCT116), interaction with double stranded DNA through in vitro assay, and molecular docking study. All complexes inhibited cell proliferation with inhibitory concentrations in the 0.5-120 µM range. While {[Pt(1,3-pd)Cl]2(µ-pz)}(2+) showed improved activity and {[Pt(en)Cl]2(µ-pydz)}(2+) showed comparable activity to that of clinically relevant cisplatin, {[Pt(en)Cl]2(µ-pydz)}(2+) was less toxic in an assay with zebrafish (Danio rerio) embryos, causing no adverse developmental effects. The in vitro cytotoxicity of all diazine-bridged dinuclear Pt(II) complexes is discussed in correlation to their structural characteristics.

Reactions and structural characterization of gold(III) complexes with amino acids, peptides and proteins.

The present review article highlights recent findings in the field of gold(III) complexes with amino acids, peptides and proteins. The first section of this article provides an overview of the gold(III) reactions with amino acids, such as glycine, alanine, histidine, cysteine and methionine. The second part of the review is mainly focused on the results achieved in the mechanistic studies of the reactions between gold(III) and different peptides and structural characterization of gold(III)-peptide complexes as the final products in these reactions. The last section of this article deals with the reactions of gold(III) complexes with proteins as primary targets for cytotoxic gold compounds. Systematic summaries of these results contribute to the future development of gold(III) complexes as potential antitumor agents and also have importance in relation to the severe toxicity of gold-based drugs.

A study of the reactions of a methionine- and histidine-containing tetrapeptide with different Pd(II) and Pt(II) complexes: selective cleavage of the amide bond by platination of the peptide and steric modification of the catalyst.

(1)H NMR spectroscopy was applied to the study of the reactions of [M(en)(H(2)O)(2)](2+) complexes (M = Pd(ii) and Pt(ii)) with the N-acetylated methionyl-glycyl-histidyl-glycineamide, MeCOMet-Gly-His-GlyNH(2). All reactions were performed in the pH range 1.5-2.0 with equimolar amounts of the [M(en)(H(2)O)(2)](2+) complex and the tetrapeptide at 60 degrees C. In all these reactions, a metal(ii) complex bound to a methionine residue affects the regioselective cleavage of the amide bond involving the carboxylic group of methionine. The priority in the cleavage of the Met-Gly amide bond in relation to the other amide bonds in this peptide is due to the high affinity of Pt(ii) and Pd(ii) ions for the sulfur donor atom. The mechanism of these hydrolytic reactions is discussed and, for its clarification, the reaction of the [Pd(en)(H(2)O)(2)](2+) complex with MeCOMet-Gly-His-GlyNH(2) was additionally investigated by potentiometric titration. The steric effects of the various palladium(ii) complexes of the type [Pd(L)(H(2)O)(2)](2+), in which L is a chelating diamine (ethylenediamine, en, 2-picolylamine, pic, or 2,2-dipyridylamine, dpa) on the hydrolytic cleavage of the amide bond involving the carboxylic group of histidine in the MeCOMet-Gly-His-GlyNH(2) tetrapeptide were also studied by (1)H NMR spectroscopy. All reactions were performed under the above-mentioned conditions and in the initial stage of these reactions, the MeCOMet-Gly-His-GlyNH(2) was reacted with an equimolar amount of the [Pt(dien)Cl](+) complex (dien is diethylenetriamine) and then the monoplatinated [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) complex was treated with an equimolar amount of [Pd(L)(H(2)O)(2)](2+). It was found that the rate of hydrolysis of the His-GlyNH(2) amide bond in [Pt(dien)(MeCOMet-Gly-His-GlyNH(2)-S)](2+) decreased from the en to the pic complex, with finally a total inhibition of this reaction with [Pd(dpa)(H(2)O)(2)](2+). These results are an important step in the study of the regioselective cleavage of peptides and proteins and in the development of new palladium(ii) complexes as artificial metallopeptidases.

Hydrolysis of the amide bond in methionine-containing peptides catalyzed by various palladium(II) complexes: dependence of the hydrolysis rate on the steric bulk of the catalyst.

(1)H NMR spectroscopy was applied to study the reactions of cis-[Pd(L)(H(2)O)(2)](2+) complexes (L is en, pic and dpa) with the N-acetylated tripeptides L-methionylglycylglycine, MeCOMet-Gly-Gly, and glycyl-L-methionyl-glycine, MeCOGly-Met-Gly. All reactions were performed in the pH range 2.0-2.5 with equimolar amounts of the cis-[Pd(L)(H(2)O)(2)](2+) complex and the tripeptide at 60 degrees C. The hydrolytic reactions of the cis-[Pd(en)(H(2)O)(2)](2+), cis-[Pd(pic)(H(2)O)(2)](2+) and cis-[Pd(dpa)(H(2)O)(2)](2+) complexes with MeCOMet-Gly-Gly were regioselective and only the amide bond involving the carboxylic group of methionine was cleaved. However, in the reactions of these three Pd(II) complexes with MeCOGly-Met-Gly, two amide bonds, Met-Gly and MeCO-Gly, were cleaved. From UV-Vis spectrophotometry studies, it was found that the rate-determining step of these hydrolytic reactions is the monodentate coordination of the corresponding Pd(II) complex to the sulfur atom of the methionine side chain. The rate of the cleavage of these amide bonds is dependent on the nature of the bidentate coordinated diamine ligand L (en>pic>dpa). The hydrolytic reaction of cis-[Pd(L)(H(2)O)(2)](2+)-type complexes with MeCOMet-Gly-Gly, containing the methionine side chain in the terminal position of the peptide, is regioselective while in the reaction of these Pd(II) complexes with MeCOGly-Met-Gly, none selective cleavage of the peptide occurs. This study contributes to a better understanding of the selective cleavage of methionine-containing peptides employing palladium(II) complexes as catalysts.

Reaction of [Pt(Gly-Gly-N,N',O)I]- with the N-acetylated dipeptide L-methionyl-L-histidine: selective platination of the histidine side chain by intramolecular migration of the platinum(II) complex.

The reaction of the monofunctional [Pt(Gly-Gly-N,N',O)I](-) complex, in which Gly-Gly is the dipeptide glycyl-glycine coordinated through two nitrogen and oxygen atoms, with the N-acetylated dipeptide L-methionyl-L-histidine (MeCOMet-His) studied by (1)H NMR spectroscopy. All reactions were carried out in 50mM phosphate buffer at pD 7.4 and at 25 degrees C. In the initial stage of the reaction, the platinum(II) complex forms the kinetically favored [Pt(Gly-Gly-N,N',O)(MeCOMet-His-S)](-) complex, with unidentate coordination of the MeCOMet-His dipeptide through the sulfur atom of the methionine residue. In the second stage of the reaction, complete intramolecular migration of the [Pt(Gly-Gly-N,N',O)] unit from the sulfur to the N3 nitrogen atom of imidazole was observed and a new platinum(II)-peptide complex, [Pt(Gly-Gly-N,N',O)(MeCOMet-His-N3)](-) was formed. In comparison with previous results obtained for the reaction of [Pt(dien)Cl](+) with different methionine- and histidine-containing peptides, this migration reaction was sufficiently fast and strongly selective to the N3 atom of the imidazole ring of the histidine side chain. This study is an important step in the development of new platinum(II) complexes for selective covalent modification of peptides and proteins.

Growth Effects of Some Platinum(II) Complexes with Sulfur-Containing Carrier Ligands on MCF7 Human Breast Cancer Cell Line upon Simultaneous Administration with Taxol.

The platinum (II)complexes, cis-[PtCl(2)(CH(3)SCH(2)CH(2)SCH(3))] (Pt1), cis-[PtCl(2)(dmso)(2)] (dmso is dimethylsulfoxide; Pt2) and cis-[PtCl(2)(NH(3))(2)] (cisplatin), and taxol (T) have been tested at different equimolar concentrations. Cells were exposed to complexes for 2 h and left to recover in fresh medium for 24, 48 or 72 h. Growth inhibition was measured by tetrazolium WST1 assay Analyses of the cell cycle, and apoptosis were performed by flow cytometry, at the same exposure times. The IC50 value of each platinum(II) complex as well as combination index (CI; platinum(II) complex + taxol) for various cytotoxicity levels were determined by median effects analysis.MCF7 cells were found to be sensitive to both Pt1 and Pt2 complexe These cisplatin analogues influenced the cell growth more effectively as compared to cisplatin. Cytotoxic effect was concentration and time-dependent. Profound growth inhibitory effect was observed for Pt1 complex, across all its concentrations at all recovery periods. A plateau effect was achieved three days after treatment at Pt1 concentrations

Ring-Opened Adducts of the Anticancer Drug Carboplatin with Sulfur Amino Acids.

Reactions of the anticancer drug carboplatin ("Paraplatin") with a variety of sulfur-containing amino acids have been investigated by (1)H and (15)N NMR spectroscopy and by HPLC. Thiols react very slowly and sulfur-bridged species containing four-membered Pt(2)S(2) rings are the predominant products. In contrast, reactions with thioether ligands are much more rapid, and kinetics for the initial stages of the reaction with L-methionine have been determined (k = 2.7 x 10(-)(3) M(-)(1) s(-)(1)). Surprisingly, very stable ring-opened species are formed such as cis-[Pt(CBDCA-O)(NH(3))(2)(L-HMet-S)] which has a half-life for Met-S,N ring-closure of 28 h at 310 K. A study of the formation of the analogous product for N-acetyl-L-methionine and its subsequent ring closure is reported. Reactions such as these may play a role in the biological activity of carboplatin.