Reduced amino acid Schiff base containing ruthenium(III) complexes: Synthesis,characterization, DNA interaction,and in vitro cytotoxicity

A number of reduced amino Schiff base ligands and corresponding ruthenium(III) complexes were designed and prepared based on the fact that amino acids not only possess multiple coordinate atoms but also improve the solubility of drugs in the body. The interaction of the complexes with calf thymus DNA was analyzed with spectroscopic methods of ultraviolet‐visible absorption spectra, DNA competitive binding with ethidium bromide, circular dichroism spectra, and DNA melting experiments, and DNA viscosity measurements, indicating that the complexes bind to DNA primarily in the grooving mode. With respect to the ligands, the cytotoxicity in vitro of the complexes against Hela, A549, and MCF‐7 cells was much enhanced, with most of the IC₅₀ values less than 50 μM or even comparable with those of cisplatin.     

A convenient and validated enantiomer separation of chiral aliphatic amines as nitrobenzoxadiazole derivatives on polysaccharide‐derived chiral stationary phases under simultaneous ultraviolet and fluorescence detection

A convenient method using a fluorogenic agent, 4‐chloro‐7‐nitro‐1,2,3‐benzoxadiazole (NBD‐Cl), was developed for enantiomer separation of chiral aliphatic amines including amino alcohols by normal high‐performance liquid chromatography. The enantiomer separation of chiral aliphatic amines as NBD derivatives was performed on six covalently bonded and four coated‐type polysaccharide‐derived chiral stationary phases (CSPs) under simultaneous ultraviolet (UV) and fluorescence detection (FLD). Among the covalently bonded CSPs, Chiralpak IE showed the best enantiomer separation for most analytes. The other CSPs also showed good enantioselectivity except for Chiralpak IB. On the other hand, Chiralpak AD‐H and Amylose‐1 generally exhibited better enantiomer separation of NBD derivatized chiral amines among the coated CSPs. The developed analytical technique was also applied to determine the optical purity of commercially available (R)‐ and (S)‐leucinol; the impurity was found to be 0.06%. The developed method was validated and proved to be an accurate, precise, sensitive, and selective method suitable for separation of chiral aliphatic amines as NBD derivatives under simultaneous UV and FLD.     

CHIRBASE,a graphical molecular database on the separation of enantiomers by liquid-, supercritical fluid-, and gas chromatography

In order to cope with the increasing number of publications on the separation of enantiomers by chromatography on a chiral stationary phase, the graphical molecular database CHIRBASE was created. In the present state, the database package covers information (structural, bibiographic, and chromatographic data) on liquid-, supercritical fluid-, and gas chromatography; other methods will follow. CHIRBASE, running on the MDL software Chembase®, meets the requirements of contemporary information management in the chemical and pharmaceutical industry. (Detailed information including a demo-version of each part of CHIRBASE can be obtained from the authors on request.) © 1993 Wiley-Liss, Inc.     

Development of stability indicating HPLC method for the separation and validation of enantiomers of miconazole

A selective and sensitive stability indicting HPLC method was developed for the analysis of enantiomers of miconazole. For this purpose, six different polysaccharide‐based chiral columns were evaluated. Optimization was performed using several polar organic and alcohol‐hydrocarbon mobile phases. As a result of optimization studies, the analysis was carried out using Lux Cellulose‐3, methanol as a mobile phase at a flow rate of 1 mL·min^?1, and the detection wavelength was arranged to 230 nm. Developed method has been fully validated according to International Council on Harmonization guidelines. Method was found linear in the concentration range of 1 to 200 μg·mL^?1. Coefficient of determination (R²) was calculated as 0.9996, intraday precision of the method was found with the RSD% of 0.56, and the recovery of the method was calculated close to 100%. Furthermore, some other validation parameters like specificity, selectivity, LOD, and LOQ were also investigated. Stability indicating capability of this method was shown by forced degradation studies, and the run time for each analysis was less than 6 minutes. As a result, simple, fast, reliable HPLC method was developed for the separation and determination of the enantiomers of miconazole. Applicability of the developed method was shown with the application of marketed pharmaceutical preparations.     

Resolution and stability of oxazepam enantiomers

A solvent mixture containing dioxane, acetonitrile, and hexane was found to be suitable as a mobile phase to resolve oxazepam enantiomers by chiral stationary phase high performance liquid chromatography using covalent Pirkle columns. The resolved oxazepam enantiomers in this solvent mixture had a racemization half-life greater than 3 days at 23°C. When desiccated at 0°C as dried residue, OX enantiomers were stable for at least 50 days with less than 2% racemization. The conditions which stabilized OX enantiomers significantly facilitated the determination of racemization half-lives of OX enantiomers in a variety of aqueous and nonaqueous solvents and at different temperatures. © 1992 Wiley-Liss, Inc.     

Synthesis,characterization and DNA binding and cleavage properties of ruthenium(II) complexes with various polypyridyls

Polypyridyl chlororuthenium(II) complexes have been synthesized and characterized. The binding mode of the complexes to DNA has been evaluated from the combined results of electronic absorption spectroscopy and viscosity measurement study. The results suggest that complexes 1, 2 and 3 bind to DNA via classical intercalation, electrostatic interaction and partial intercalation mode, respectively. Complex 2 shows less affinity for DNA. Cleavage of pUC19 DNA by complexes has been checked using gel electrophoresis. The data disclose that complex 1 has the highest cleaving ability.     

Synthesis of an amphiphilic ruthenium complex with swallow-tail bipyridyl ligand and its application in nc-DSC

An amphiphilic swallow-tail bipyridyl ligand, 4,4′-bis(dihexylmethyl)-2,2′-bipyridine, and its heteroleptic ruthenium (II) complex were synthesized starting from dichloro-(p-cymene)ruthenium (II) dimer. The complex was characterized by UV/Vis and FTIR spectrophotometers, NMR spectroscopy and cyclic voltammetry. The performance of this complex as charge transfer photosensitizer in nc-TiO₂ based dye sensitized solar cells was studied under standard AM 1.5 sunlight and by using an electrolyte consisting of 0.6 M N-methyl-N-butyl imidazolium iodide (BMII), 0.1 M LiI, 0.05 M I₂, 0.5 M 4-tert-butyl pyridine (TBP) in acetonitrile. The complex, CS9 in DMF, gave a photocurrent density of 12.62 mA/cm², 630 mV open circuit potential and 0.62 fill factor yielding 5.68% efficiency.     

Use of a naphthylethylcarbamoylated-β-cyclodextrin chiral stationary phase for the separation of drug enantiomers and related compounds by sub- and supercritical fluid chromatography

Enantiomeric separation of a variety of drugs and related compounds was achieved on an (S)-naphthylethylcarbamoylated-β-cyclodextrin (S-NEC-CD) chiral stationary phase (CSP) using sub- and supercritical fluid chromatography (SFC). Compounds previously resolved on native or derivatized cyclodextrin CSPs in liquid chromatography (LC) using reversed phase or polar organic mobile phase modes could be resolved in SFC using a simple carbon dioxide/methanol eluent. Resolution of cromakalim, which is not possible on the S-NEC-CD column in LC, was readily accomplished in SFC. The importance of modifier, temperature, and pressure was assessed in relation to retention, selectivity, and resolution. The nature of the modifier and the modifier concentration were found to be crucial parameters. © 1996 Wiley-Liss, Inc. Contribution of the National Institute of Standards and Technology. Not subject to copyright.     

Synthesis, chiral HPLC resolution and configuration assignment of 1-phenylglyceryl trinitrate stereomers

As an introductory study of in vitro vasodilating activity, the access to the four stereomers of 1-phenylglyceryl trinitrate is described using achiral and chiral chromatography. For semi-preparative separation of the enantiomers, a Chiralcel OD (250 x 10 mm, 10 microm) was used. Catalytic reduction leading to the corresponding stereomers of 1-phenylglycerol allowed absolute configuration assignments. The same methods were used for the separation and configuration assignment of the enantiomers of 3-phenylpropane-1,2-diyl dinitrate.     

Enantiomeric Separations of Ruthenium (II) Polypyridyl Complexes Using HPLC With Cyclofructan Chiral Stationary Phases

The enantiomeric separation of 21 ruthenium (II) polypyridyl complexes was achieved with a novel class of cyclofructan‐based chiral stationary phases (CSPs) in the polar organic mode. Aromatic derivatives on the chiral selectors proved to be essential for enantioselectivity. The R‐napthylethyl carbamate functionalized cyclofructan 6 (LARIHC CF6‐RN) column proved to be the most effective overall, while the dimethylphenyl carbamate cyclofructan 7 (LARIHC CF7‐DMP) showed complementary selectivity. A combination of acid and base additives was necessary for optimal separations. The retention factor vs. acetonitrile/methanol ratio plot showed a U‐shaped retention curve, indicating that different interactions take place at different polar organic solvent compositions. The separation results indicated that π–π interactions, steric effects, and hydrogen bonding contribute to the enantiomeric separation of ruthenium (II) polypyridyl complexes with cyclofructan chiral stationary phases in the polar organic mode. Chirality 27:64–70, 2015. © 2014 Wiley Periodicals, Inc.     

Chiral separation of flurbiprofen enantiomers by preparative and simulated moving bed chromatography

This study presents the chiral resolution of flurbiprofen enantiomers by preparative liquid chromatography using the simulated moving bed (SMB) technology. Flurbiprofen enantiomers are widely used as nonsteroidal anti‐inflammatory drugs, and although demonstrate different therapeutic actions, they are still marketed as a racemic mixture. The results presented here clearly show the importance of the selection of the proper solvent composition for the preparative separation of flurbiprofen enantiomers. Chiral SMB separation is carried out using a laboratory‐scale unit (the FlexSMB‐LSRE®) with six columns, packed with the Chiralpak AD® stationary phase (20 μm). Results presented include the experimental measurement of equilibrium and kinetic data for two very different solvent compositions, a traditional high hydrocarbon content [10%ethanol/90%n‐hexane/0.01% trifluoroacetic acid (TFA)] and a strong polar organic composition (100%ethanol/0.01%TFA). Experimental data, obtained using the two mobile phase compositions, are used to predict and optimize the SMB operation. After selecting 10%ethanol/90%n‐hexane/0.01%TFA as the most appropriate solvent composition, three feed concentrations of racemic flurbiprofen were considered. Using 40 g/l of racemic flurbiprofen feed solution, the purities for both outlet streams were above 99.4%, the productivity was 13.1 g_feed/(L_bed h), and a solvent consumption of 0.41 L_solvent/g_feed was achieved. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Enantioseparation of benzoxazolinone aminoalcohols and their aminoketone precursors,potential adrenergic ligands,by analytical and preparative liquid chromatography on amylose chiral stationary phases and characterization of the enantiomers

To obtain milligram amounts of the enantiomers of benzoxazolinone derivatives to be tested for binding to adrenergic sites, analytical HPLC methods using derivatized amylose chiral stationary phases were developed for the direct enantioseparation of benzoxazolinone aminoalcohols and their aminoketone precursors, derivatives with one or two chirals centers. The separations were made using normal phase methodology with a mobile phase of n‐hexane‐alcohol (ethanol, 1‐propanol, or 2‐propanol) in various proportions, and silica‐based amylose (tris‐3, 5‐dimethylphenylcarbamate) Chiralpak AD and (tris‐(S)‐1‐phenylethylcarbamate) Chiralpak AS columns. The effects of concentration of various aliphatic alcohols in the mobile phase were studied. The best separation was achieved on Chiralpak AS, so preparative HPLC was set up with this chiral stationary phase using a mobile phase consisting of n‐hexane‐alcohol using isocratic conditions and multiple repetitive injections. Physicochemicals properties of enantiomers were reported The effect of structural features of the solutes on discrimination between the enantiomers was examined. Limit of detection (LD) and limit of quantification (LQ) were determined using both ultra‐violet (UV) and evaporative light‐scattering detection (ELSD). Chirality, 2009. © 2008 Wiley‐Liss, Inc.     

Synthesis and X‐ray diffraction study of a chiral bis‐phosphahelicene palladium (II) complex

As a complement to our previous studies on the development of a class of chiral phosphahelicenes, this article discloses the synthesis, spectroscopic, and structural characterizations of a new phosphahelicene transition metal complex. It demonstrates the ability of these hindered chiral ligands to coordinate Pd (II) in trans‐complexes Cl₂Pd(L*)₂. In the solid state, the complex adopts a C2‐symmetric arrangement with two ligands facing each other on the same face of the coordination plane. X‐Ray data highlight bending of the Pd (II) unit from the expected planar coordination geometry that might be due to a significant π‐π stacking effect between the central rings of two helical units.     

Enantiomeric separation of β‐blockers and tryptophan using heparin as stationary and pseudostationary phases in capillary electrophoresis

The separation methods of the enantiomers of two β‐blockers and tryptophan were studied using capillary electrochromatography with heparin covalently as well as non‐covalently, bonded onto the capillary inner wall as stationary phase and electrokinetic chromatography with heparin as pseudostationary phase. In the case of heparin, used as a stationary phase, the method was unable to resolve enantiomers in both cases β‐blockers and tryptophan. On the other hand, when heparin was used as a pseudostationary phase, the resolution of the enantiomers was obtained only with 3‐aminopropyltriethoxysilane which were immobilised onto the inner phase of the capillary. The results of this study let us infer that the electrostatic, hydrophobic, and steric interactions were involved in the separation mechanisms. The separation was achieved in less than 10 minutes under the optimized conditions: 30 mM phosphate buffer (pH 2.5) with the adding of 15 mg/mL of heparin at 15°C and 10 kV. The usefulness of heparin as a chiral selector both in electrokinetic chromatography using 3‐aminopropyltriethoxysilane attached to the capillary was demonstrated for the first time. The developed method was powerful, sensitive, and fast, and it could be considered an important alternative to conventional methods used for chiral separation.     

Synthesis of novel mononuclear and dinuclear ruthenium(II) complexes with terpyridine and acetylacetonate ancillary ligands and cyanamide derivative ligands

Several new mononuclear and dinuclear ruthenium(II) complexes - incorporating 2,2′:6′,2″-terpyridine and acetylacetonate as ancillary ligands and phenylcyanamide derivative ligands - of the type [Ru(tpy)(acac)(L)] and [{Ru(tpy)(acac)}₂(μ-L′)] (where tpy = 2,2′:6′,2″-terpyridine, acac = acetylacetonate, L = hmbpcyd = 4-(3-hydroxy-3-methylbutynyl)phenylcyanamide anion (2) and epcyd = 4-ethynylphenylcyanamide anion (3) and L′ = bcpda = bis(4-cyanamidophenyl)diacetylene dianion (4) and bcpea = 9,10-bis(4-cyanamidophenylethynyl)anthracene dianion (5)) were synthesized in a stepwise manner starting from [Ru(tpy)(acac)(Ipcyd)] (1), where Ipcyd = 4-iodophenylcyanamide anion. Tetraphenylarsonium salts of the phenylcyanamide derivative ligands were also prepared. The four complexes have been characterized by UV-Vis, IR, ES-MS, electrochemistry and ¹H NMR. Mononuclear complexes 2 and 3 were further characterized by ¹³C NMR. The single crystal X-ray structure of 2 was determined, it crystallized with one molecule of water with empirical formula of C₃₂H₃₁N₅O₅Ru, in a monoclinic crystal system and space group of P2₁/n with a = 17.642(5) Å, b = 9.634(2) Å, c = 20.063(7) Å, β = 92.65(3)°, V = 3406(2) Å³ and Z = 4. The structure was refined to a final R factor of 0.040. The Ru(III/II) couple of 1-3 appeared around 0.34 V versus the saturated calomel electrode in dimethylformamide and at a slightly higher potential, around 0.36-0.37 V for 4 and 5. Spectroelectrochemical studies were also performed for 4 and 5, no intervalence transition was observed despite all attempts.     

Synthesis,characterization, DNA interaction,and cytotoxicity of novel Pd(II) and Pt(II) complexes

Four complexes [Pd(L)(bipy)Cl]·4H₂O (1), [Pd(L)(phen)Cl]·4H₂O (2), [Pt(L)(bipy)Cl]·4H₂O (3), and [Pt(L)(phen)Cl]·4H₂O (4), where L = quinolinic acid, bipy = 2,2’-bipyridyl, and phen = 1,10-phenanthroline, have been synthesized and characterized using IR, ¹H NMR, elemental analysis, and single-crystal X-ray diffractometry. The binding of the complexes to FS-DNA was investigated by electronic absorption titration and fluorescence spectroscopy. The results indicate that the complexes bind to FS-DNA in an intercalative mode and the intrinsic binding constants K of the title complexes with FS-DNA are about 3.5?×?10⁴ M^?1, 3.9?×?10⁴ M^?1, 6.1?×?10⁴ M^?1, and 1.4?×?10⁵ M^?1, respectively. Also, the four complexes bind to DNA with different binding affinities, in descending order: complex 4, complex 3, complex 2, complex 1. Gel electrophoresis assay demonstrated the ability of the Pt(II) complexes to cleave pBR322 plasmid DNA.     

Gas-chromatographic separation of tri(hetero)halogenomethane enantiomers

Five-atomic tri(hetero)halogenomethanes represent the simplest class of non-isotopic small chiral molecules suitable for the study of fundamental aspects of chirality. The analytical gas-chromatographic separation of the enantiomers of bromochlorofluoromethane 1 and of chlorofluoroiodomethane 2 on the immobilized chiral stationary phase octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-gamma-cyclodextrin 3, chemically linked to polydimethylsiloxane, is described. By temperature-dependent thermodynamic measurements very low isoenantioselective temperatures T(iso) are found and for optimum enantiomeric separations cryogenic temperatures are required. The ee values of enantiomerically enriched tri(hetero)halogenomethanes 1 and 2 are determined and relative configurations are correlated with the chromatographic elution order of 1 and 2 on 3.     

Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose–based chiral stationary phase

A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5‐dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n‐hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2 mL/min. The limit of detection and limit of quantification of the S‐enantiomer were found to be 0.45 and 1.5 μg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20°C to 50°C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters ΔH°, ΔS°, and ΔG° were evaluated from van't Hoff plots,(Ink′ _versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose–based chiral stationary phase     

Synthesis and chemical characterization of Cu, Ni and Zn complexes of 3,5-bis(2′-pyridyl)-1,2,4-oxadiazole and 3-(2′-pyridyl)5-(phenyl)-1,2,4-oxadiazole ligands

The synthesis and structural characterization of Ni^II, Cu^II and Zn^II complexes of two chelating 1,2,4-oxadiazole ligands, namely 3,5-bis(2′-pyridyl)-1,2,4-oxadiazole (bipyOXA) and 3-(2′-pyridyl)5-(phenyl)-1,2,4-oxadiazole (pyOXA), is here reported. The formed hexacoordinated metal complexes are [M(bipyOXA)₂(H₂O)₂](ClO₄)₂ and [M(pyOXA)₂(ClO₄)₂], respectively (M = Ni, Cu, Zn). X-ray crystallography, ¹H and ¹³C NMR spectroscopy and C, N, H elemental analysis data concord in attributing them an octahedral coordination geometry. The two coordinated pyOXA ligands assume a trans coplanar disposition, while the two bipyOXA ligands are not. The latter result is a possible consequence of the formation of H-bonds between the coordinated water molecules and the nitrogen atom of the pyridine in position 5 of the oxadiazole ring. The expected splitting of the d metal orbitals in an octahedral ligand field explains the observed paramagnetism of the d⁸ and d⁹ electron configuration of the nickel(II) and copper(II) complexes, respectively, as determined by the broadening of their NMR spectra.