Hydrolysis of the amide bond in N-acetylated l-methionylglycine catalyzed by various platinum(II) complexes under physiologically relevant conditions

The hydrolytic reactions between various Pt(II) complexes of the type [Pt(L)Cl₂] and [Pt(L)(CBDCA-O,O′] (L is ethylenediamine, en; (±)-trans-1,2-diaminocyclohexane, dach; (±)-1,2-propylenediamine, 1,2-pn and CBDCA is the 1,1-cyclobutanedicarboxylic anion) and the N-acetylated l-methionylglycine dipeptide (MeCOMet-Gly) were studied by ¹H NMR spectroscopy. All reactions were realized at 37 °C with equimolar amounts of the Pt(II) complex and the dipeptide at pH 7.40 in 50 mM phosphate buffer in D₂O. Under these experimental conditions, a very slow cleavage of the Met-Gly amide bond was observed and this hydrolytic reaction proceeds through the intermediate [Pt(L)(H₂O)(MeCOMet-Gly-S)]⁺ complex. In general, it can be concluded that faster hydrolytic cleavage of the MeCOMet-Gly dipeptide was observed in the reaction with the chloride complex than with corresponding CBDCA Pt(II) complexes. The steric effects of the Pt(II) complex on the hydrolytic cleavage of the amide bond in the MeCOMet-Gly dipeptide were also investigated by ¹H NMR spectroscopy. It was found that the rate of hydrolysis decreases as the steric bulk of the CBDCA and chlorido Pt(II) complexes increase (en > 1,2-pn > dach). These results contribute to a better understanding of the toxic side effects of Pt(II) antitumor drugs and should be taken into consideration when designing new potential Pt(II) antitumor drugs with preferably low toxic side effects.     

A tethered aminohydroxylation route to l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C18-phytosphingosines

A concise and highly efficient synthesis of l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C₁₈-phytosphingosines has been achieved. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation as the key steps.     

Phase behavior of biodegradable amphiphilic poly(l,l-lactide)-b-poly(ethylene glycol)-b-poly(l,l-lactide)

This study describes the miscibility phase behavior in two series of biodegradable triblock copolymers, poly(l-lactide)-block-poly(ethylene glycol)-block-poly(l-lactide) (PLLA-PEG-PLLA), prepared from two di-hydroxy-terminated PEG prepolymers (M_n = 4000 or 600 g mol⁻¹) with different lengths of poly(l-lactide) segments (polymerization degree, DP = 1.2-145.6). The prepared block copolymers presented wide range of molecular weights (800-25,000 g mol⁻¹) and compositions (16-80 wt.% of PEG). The copolymer multiphases coexistance and interaction were evaluated by DSC and TGA. The copolymers presented a dual stage thermal degradation and decreased thermal stability compared to PEG homopolymers. In addition, DSC analyses allowed the observation of multiphase separation; the melting temperature, T_m, of PLLA and PEG phases depended on the relative segment lengths and the only observed glass transition temperature (T_g) in copolymers indicated miscibility in the amorphous phase.     

Intermolecular/interionic interactions in l-isoleucine-, l-proline-, and l-glutamine-aqueous electrolyte systems

Speed of sound and density values for ternary systems (amino acid + salt + water): l-isoleucine/l-proline/l-glutamine in aqueous solutions of 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ have been measured for several concentrations of amino acids at different temperatures (303.15, 308.15, 313.15, 318.15, and 323.15 K). Using speed of sound and density data, the thermodynamic parameters such as isentropic compressibility (κ_s), change in isentropic compressibility (Δκ_s) and relative change (Δκ_s/κ₀) in isentropic compressibility have been computed. The isentropic compressibility values decrease with increase in the amino acid concentration as well as with temperature. The decrease in κ_s values with increase in concentration of l-isoleucine/l-proline/l-glutamine in 1.5 M KCl, 1 M KNO₃, and 0.5 M K₂SO₄ has been ascribed to an increase in the number of incompressible zwitterions in solutions, and the formation of ‘zwitterions-ions’ and ‘zwitterions-water dipole’ entities in solutions. The decrease in κ_s values with increase in temperature has been attributed to the corresponding decrease of κ_relax (a relaxational part of compressibility), which is dominant over the corresponding increase of κ_∞ (an instantaneous part of compressibility). The trends of variation of Δκ_s and Δκ_s/κ₀ with variations in solute concentration and temperature have also been discussed in terms of solute-solute and solute-solvent intermolecular/interionic interactions operative in the systems.     

Controlled emission of platinum(II) terpyridyl complexes with poly-l-glutamic acid

Poly-l-glutamic acid, P(Glu), bearing multiple negatively charged side chains served as a polymeric spatially aligned scaffold for the aggregation of positively charged platinum(II) complexes [Pt(trpy)CCR](OTf) (trpy = 2,2′,6′,2″-terpyridine; R = Ph (PtH), PhC₁₂H₂₅-p (PtC₁₂)) through electrostatic interaction, resulting in tunable emission properties. PtC₁₂ was found to exhibit gradual increase in the emission intensity based on the triplet metal-metal-to-ligand charge transfer (³MMLCT) in a tris/HCl buffer (pH 7.6)/MeOH (v/v = 1/14) solution with concomitant decrease in the emission intensity based on the triplet metal-to-ligand charge transfer (³MLCT)/the triplet ligand-to-ligand charge transfer (³LLCT) as the amount of P(Glu) was increased. Such synergistic effect was not observed in the case of PtH, wherein the emission intensity based on ³MLCT/³LLCT was increased by the increase in the amount of P(Glu), indicating that alkyl long chain of PtC₁₂ is considered to play an important role in the aggregation of the platinum(II) terpyridyl moieties to show Pt(II)-Pt(II) and π-π interactions.     

Synthesis of two dicopper(II) complexes of l-carnitine: The first structural determination of a metal complex containing l-carnitine

Two dimeric copper(II) complexes of the biologically important compound l-carnitine were isolated from ethanolic and aqueous solutions with formulas [Cu₂(l-carnitine)₂Cl₂(H₂O)₂] · Cl₂ (complex 1) and [Cu₂(l-carnitine)₄(H₂O)₂] · (ClO₄)₄ · H₂O · CH₂Cl₂ (complex 2), respectively. Complex 1 was characterized in solid state by elemental analysis, thermal analysis (TG, DTG), IR and EPR as well as in solution with cationic and anionic ESMS, EPR, NMR and UV–Vis spectroscopies. For complex 2, crystals were isolated after recrystallization and characterized by X-ray crystallography, elemental analysis, IR and NMR spectroscopies.     

High selectivity for l-cysteine residue at axial solvated site of trigonal-bipyramidal palladium(II) complex with tripodal tetradentate phosphine

The five-coordinate trigonal-bipyramidal palladium(II) and platinum(II) complexes with sulfur-coordinated glutathione at the axial position, [Pd(gluta)(pp₃)](BF₄) and [Pt(gluta)(pp₃)](PF₆) (gluta = glutathionate, pp₃ = tris[2-(diphenylphosphino)ethyl]phosphine), were prepared and characterized by ³¹P NMR spectroscopy. The dimeric square-planar platinum(II) complex [Pt(pp₃)]₂(PF₆)₄ gave the monomeric five-coordinate solvated complex, [Pt(pp₃)(CH₃CN)]²⁺, in acetonitrile. Extraction experiments for amino acids from the aqueous solution to the chloroform layer were carried out by using [Pd(pp₃)(CH₃CN)]²⁺, [Pt(pp₃)(CH₃CN)]²⁺, and [Pd(p₃)(CH₃CN)]²⁺ (p₃ = bis[2-(diphenylphosphino)ethyl]phenylphosphine) as extractants. High selectivity for the thiolate sulfur atom in l-cysteinate was observed at the solvated coordination site in [Pd(pp₃)(CH₃CN)]²⁺. The selectivity was applied to extraction of l-cysteinate from a mixture of some amino acids and, further, the reduced form of glutathionate from a mixture of the reduced and oxidized forms of glutathione.     

Short asymmetric synthesis of (S,S)-PDP using l-prolinol derivative as economic starting material

(S,S)-PDP (5d) and its backbone (2S,2′S)-bipyrrolidine (1) have been extensively applied as the scaffold of various chiral ligands in catalytic asymmetric syntheses. In this study, new short asymmetric syntheses of these two important C₂-symmetrical nitrogen heterocycles have been accomplished employing economically available l-prolinol derivative 10 as the starting material. Excellent diastereoselectivity was achieved of the key Grignard addition to imine intermediate utilizing (S)-N-tert-butanesulfinamide as the chiral auxiliary.     

New Sn(IV) and Ti(IV) bis(trimethylsilyl)amides in d,l-lactide polymerization, SEM characterization of polymers

Ring-opening polymerization of d,l-lactide initiated with new chlorotris(bis(trimethylsilyl) amido) tin(IV), tetrakis(bis(trimethylsilyl)amido) tin(IV) and titanium(IV) was investigated. New complexes reveal practically quantitative conversion degrees and produced polymers with higher molecular weight with respect to reference alkoxo-species.The X-ray crystal structure of chlorotris(bis(trimethylsilyl)amido) tin (IV) was investigated. Axial enantiomerism of [SnCl{N(SiMe₃)₂}₃] molecules in solution was studied by high-field dynamic NMR, the value of Gibbs activation energy ΔG^‡ = 59.5 kJ/mol.Field emission SEM investigation of bulk polymer samples and thin films on conductive Al foil revealed a stratified fibrous textures in the bulk polymers, as well as nanoscaled topographical features due to coils and entanglements of individual macromolecules in thin films.     

Synthesis of a heterodinuclear ruthenium(II)–platinum(II) complex linked by l-cysteine methyl ester

A potential anticancer heterodinuclear ruthenium(II)–platinum(II) complex, [ruthenium(II)(4,4′-dimethyl-2,2′-bipyridine)₂(5-(l-cysteine-methyl ester)-1,10-phenanthroline)-trans-chlorodiammineplatinum(II)] chloride, [Ru(Me₂bipy)₂(5-(l-cysteine-Me)-phen)-trans-Pt(NH₃)₂Cl]Cl₃, was synthesised. l-Cysteine methyl ester was used to link the two metal centres, as more conventional straight chain diaminoalkanes and 2-mercaptoethylamine failed to couple to the phenanthroline ligand. From the precursor mononuclear ruthenium(II) complexes, which were separated into their Δ- and Λ-isomers by column chromatography, the dinuclear complex was synthesised and characterised by ¹H and ¹³C NMR, UV–Vis, circular dichroism, fluorescence and electrospray ionisation mass spectrometry.     

Synthesis,spectroscopic and structural characterization of diphenyltin(IV) complexes of acetone Schiff bases of S-alkyldithiocarbazates

New diphenyltin(IV) complexes of empirical formula, [Sn(C₆H₅)₂(NS)Cl] (NS = anionic forms of the acetone Schiff bases of S-methyl or S-benzyldithiocarbazate) have been prepared and characterized by IR, NMR and Mössbauer spectroscopic techniques. The crystal and molecular structures of the acetone Schiff bases of S-methyldithiocarbazate (Hacsme) and S-benzyldithiocarbazate (Hacsbz) and their tin(IV) complexes have been determined by X-ray diffraction. In the solid state, both the Schiff bases exist in their thioketo tautomeric forms with the azomethine nitrogen atom trans to the thione sulfur atom but in the tin(IV) complexes they are present in their deprotonated ene-thiolate forms being coordinated to the tin atom as bidentate chelating agents via the azomethine nitrogen and thiolate sulfur atoms. The tin atom adopts a five-coordinate, approximately trigonal bipyramidal geometry, with the thiolate sulfur atom of the Schiff base and the two phenyl groups occupying the equatorial positions. The azomethine nitrogen atom and the chlorine ligand occupy axial positions. The distortion from a regular trigonal bipyramidal or a square-pyramidal geometry is attributed to the restricted bite sizes of the five-membered chelate rings.     

Formation and structures of Pd(II) N,S-heterocyclic carbene-pyridyl mixed-ligand complexes

Mononuclear mixed-ligand complexes of Pd(II) containing a N,S-heterocyclic carbene (NSHC) with a secondary alkyl N-substituent and pyridyl ligand, with the general formula [PdI₂(C₁₀H₁₁NS)L] (C₁₀H₁₁NS = 3-isopropylbenzothiazolin-2-ylidene; L = pyridine, 2-aminopyridine, 3-iodopyridine and 4-tert-butyl-pyridine) have been synthesized and characterized by X-ray single-crystal crystallography. Both solution and solid-state structures, as evident from their ¹H NMR spectra and X-ray structures, show anagostic γ-hydrogen interactions of metal with methine of the substituent on the carbene or pyridyl ligand giving 5-membered-chelate-like structures.     

Intermolecular/interionic interactions in l-leucine-, l-asparagine-, and glycylglycine-aqueous electrolyte systems

Ultrasonic velocity and density values have been measured for ternary systems (amino acid/di-peptide + salt + water): l-leucine/l-asparagine/glycylglycine each in 1.5 M aqueous solutions of NaCl or NaNO₃ or KNO₃ used as solvents for several concentrations of amino acids/di-peptide at different temperatures in the range of 298.15-323.15 K. The ultrasonic velocity values have been found to increase with increase in amino acids/di-peptide concentration and temperature in all the systems. The increase in ultrasonic velocity with increase in concentration has been discussed in terms of electrostatic interactions occurring between terminal groups of zwitterions (NH₄⁺ and COO⁻) and Na⁺, K⁺, Cl⁻, NO₃⁻ ions. The interactions of water dipoles with cations/anions and with zwitterions have also been taken into consideration. It has been observed that the ion-zwitterion and ion-dipole attractive forces are stronger than those of ion-hydrophobic repulsive forces. These interactions comprehensively introduce the cohesion into solutions under investigation. The cohesive forces are further enhanced on successive increases in solute concentration. Using ultrasonic velocity and density data, the parameters such as isentropic compressibility (κ_s), change (Δκ_s) and relative change (Δκ_s/κ₀) in isentropic compressibility, specific acoustic impedance (Z) and relative association (RA) have been computed. The isentropic compressibility values decrease with increase in the concentration of solutes as well as with temperature. The decrease in κ_s values with increase in concentration of l-leucine, l-asparagine and glycylglycine in 1.5 M aqueous solutions of NaCl, NaNO₃ and KNO₃ have been explained in terms of an increase in the number of incompressible molecules/zwitterions in solutions and the formation of compact zwitterions-water dipole and zwitterions-ions structures in solutions. The decrease in κ_s values with increase in temperature has been attributed to the corresponding decrease of κ_relax. (relaxational part of compressibility)_, which is dominant over the corresponding increase of κ_∞ (instantaneous part of compressibility). The trends of variations of Δκ_s, Δκ_s/κ₀, Z and RA with change of concentration and temperature have also been interpreted in terms of various intermolecular/interionic interactions existing in the systems.     

Noncovalent interactions and copper(II) coordination in systems containing l-aspartic acid and triamines

Interactions between l-aspartic acids (Asp) and polyamines (PA): 3,3-tri (1,7-diamino-4-azaheptane) or spermidine (Spd, 1,8-diamino-4-azaoctane) are investigated in metal-free systems as well as between Cu(II) ions in ternary systems with Asp and 3,3-tri or Spd. The composition and stability constants of the complexes formed have been determined by a potentiometric method, while the centres of interactions in the ligands have been identified by NMR, UV–Vis, IR, and EPR spectroscopy. The centres are the potential sites of metal ion coordination. In the Asp/PA systems, formation of molecular complexes (Asp)H_x(PA) was observed. Comparison of the log K_e of the adducts showed that the stability of the adducts significantly depends on the steric factor contributed by the length of PA. In the (Asp)H₃(PA) species, an inversion effect was observed where one of the amine groups (deprotonated) of 3,3-tri or Spd becomes a negative reaction centre and reacts with the protonated amino group of Asp. Therefore, depending on pH, the amino group of the PA can act as a positive or negative reaction centre. In the ternary systems of Cu(II)/Asp/PA the heteroligand-protonated complexes and molecular complexes are formed. In the molecular complexes ML?L′, where L = Asp and L′ = PA, the metallation involves oxygen atoms from the carboxyl groups and the amino group of the amino acid, while the fully protonated PA is located outside the inner coordination sphere and reacts with the anchoring binary complex CuH(Asp) or Cu(Asp). Introduction of metal ions into the Asp/3,3-tri system was found to change the character of the interaction and in the Cu(Asp)H₂(3,3-tri) complex, the oxygen atoms from the Asp carboxyl groups do not take part in coordination.     

Thermodynamic properties of hydrated sodium l-threonate Na(C4H7O5)·H2O(s)

Low-temperature heat capacities of the compound Na(C₄H₇O₅)·H₂O(s) have been measured with an automated adiabatic calorimeter. A solid-solid phase transition and dehydration occur at 290-318 K and 367-373 K, respectively. The enthalpy and entropy of the solid-solid transition are Δ_transH_m = (5.75 ± 0.01) kJ mol⁻¹ and Δ_transS_m = (18.47 ± 0.02) J K⁻¹ mol⁻¹. The enthalpy and entropy of the dehydration are Δ_dH_m = (15.35 ± 0.03) kJ mol⁻¹ and Δ_dS_m = (41.35 ± 0.08) J K⁻¹ mol⁻¹. Experimental values of heat capacities for the solids (I and II) and the solid-liquid mixture (III) have been fitted to polynomial equations.     

Chemical, spectroscopic characterization, DFT studies and initial pharmacological assays of a silver(I) complex with N-acetyl-l-cysteine

A new silver(I) complex with N-acetyl-l-cysteine (NAC) of composition AgC₅H₈NO₃S·H₂O was synthesized and characterized by a set of chemical and spectroscopic measurements. Solid-state ¹³C nuclear magnetic resonance (SSNMR) and infrared (IR) analyses indicate the coordination of the ligand to Ag(I) through the sulfur atom. The Ag-NAC complex is slightly soluble in dimethyl sulfoxide. It is insoluble in water, methanol, ethanol, acetone and hexane. Antibacterial activity of the silver complex with N-acetyl-l-cysteine (Ag-NAC) was evaluated by antibiogram assays using the disc diffusion method. The compound showed an effective antibacterial activity against Staphylococcus aureus (Gram-positive), Escherichia coli and Pseudomonas aeruginosa (Gram-negative) bacterial cells. Biological analysis for evaluation of a potential cytotoxic effect of Ag-NAC was performed using HeLa cells derived from human cervical adenocarcinoma. The complex presented a significant cytotoxic activity, inducing 80% of cell death at a concentration of 200 μmol L⁻¹.     

Synthesis,characterization and bioactivity of mixed-ligand Cu(II) complexes containing Schiff bases derived from S-benzyldithiocarbazate and saccharinate ligand and the X-ray crystal structure of the copper-saccharinate complex containing S-benzyl-β-N-(acetylpyrid-2-yl)methylenedithiocarbazate

Mixed-ligand complexes of general formula, [Cu(NNS)(sac)] (NNS′ = S-benzyl-β-N-(2-acetylpyrid-2-yl)methylenedithiocarbazate, NNS″ = S-benzyl-β-N-(2-benzoylpyrid-2-yl)methylenedithiocarbazate and NNS? = S-benzyl-β-N-(6-methylpyrid-2-yl)methylenedithio-carbazate, sac = the saccharinate anion) have been synthesized by reacting [Cu(sac)₂(H₂O)₄] · 2H₂O with the appropriate ligands in ethanol and characterized by various physico-chemical techniques. Magnetic and spectral evidence indicate that the complexes are four-coordinate in which the Schiff bases coordinate as NNS ligands and the sac- anion coordinates as a unidentate N-donor ligand. An X-ray crystallographic structural analysis of [Cu(NNS′)(sac)] shows that the complex has a distorted square-planar geometry with the Schiff base coordinated to the copper (II) ion as a uninegatively charged tridentate chelating agent via the pyridine nitrogen atom, the azomethine nitrogen atom and the thiolate sulphur atom while the fourth coordination position is occupied by the N-bonded saccharinate anion. The complexes have been evaluated for their biological activities against selected pathogens and cancer cell lines. They display weak activity against the pathogenic bacteria and fungi. The complexes were highly active against the leukemic cell line (HL-60) but only [Cu(NNS′)(sac)] was found to exhibit strong cytotoxicity against the ovarian cancer cell line (Caov-3). All complexes were inactive against the breast cancer cell line (MCF-7).     

An amperometric method for the determination of trace mercury(II) by formation of complexes with l-tyrosine

A selective and sensitive amperometric method of analysis has been developed for determination of the trace amounts of mercury in waters at a platinum electrode based on the effect of the presence of mercury ions on the current due to oxidation of l-tyrosine. A decrease of signal was observed due to the formation of a complex of tyrosine with the Hg(II) ion adsorbed on the electrode surface. Several parameters were varied, such as applied potential, pH and concentration of tyrosine. The calibration plot was linear in the range from 0.02 to 3 μmol l⁻¹ Hg(II) with r=0.997 and the detection limit (3σ) was 0.014 μmol l⁻¹; the relative standard deviation was 2.2%. The study of interferences from other metal ions revealed a good selectivity of this method towards mercury(II). The stoichiometry of the mercury-tyrosine complex was determined to be 1:2 and the formation constant 627±19. Formation of complexes with mercury ions was also demonstrated with several catechol compounds and other amino acids. The method was applied to the analysis of contaminated waters.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.