Synthesis of Novel Asymmetrical 1,4‐Dihydropyridine Derivatives

Asymmetrical 1,4‐dihydropyridine esters 3a and 3i–k were synthesized from the symmetrical precursor 1 through the intermediate 2‐bromomethyl derivative 2. Then, compound 3a was subjected to a different transformation for preparation of 1,4‐dihydropyridine derivatives 3b–h.     

Facile Synthesis and Anticancer Activity Study of Novel Series of Substituted and Fused Coumarin Derivatives

Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10 , 12 , 13 , 16–19 , 21 , 23–32 , 38 , and 42–45 . In addition, different pyranocoumarin derivatives either substituted as in compounds 2 , 3 , and 6 or fused as compounds 33–36 , pyranoxanthene analogues such as compounds 4 and 46 , coumarinotriazolothiadiazine derivative 8 , coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty‐eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16 , 40 , and 43 bearing 4‐chlorophenyl‐2‐aminopyridine‐3‐carbonitrile attached to C₆ position, fused pyrazolone ring or attached to 4‐chlorophenyl‐2‐oxo‐dihydropyridine‐3‐carbonitrile at C₃ position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.     

Capillary electrophoretic enantioseparation of m‐nisoldipine using two different β‐cyclodextrins

The methods for the enantioseparation of m‐nisoldipine, a new 1,4‐dihydropyridine calcium ion antagonist, were developed. The elaborated methods of m‐nisoldipine enantiomers separation were successfully performed using an anionic CD–sulfobutyl ether‐β‐CD (SBE‐β‐CD) or carboxymethyl‐β‐CD as chiral selector. However, the results indicated that SBE‐β‐CD was a better chiral selector for enantioseparation of the neutral m‐nisoldipine. Furthermore, comparing the two SBE‐β‐CDs, the derivative with a higher degree of substitution (DS) of 7.0 induced better enantioresolution than the one with low DS (4.0). In addition, possible chiral recognition mechanisms of dihydropyridines were discussed.     

Identification of degradation products in stressed tablets of Rabeprazole sodium by HPLC‐hyphenated techniques

Three unknown impurities of Rabeprazole, a proton pump inhibitor, were formed in the formulated drug under the stress conditions, [40 °C/75% relative humidity (RH) for 6 months] with relative retention times (RRTs) 0.17, 0.22 and 0.28. The Impurity‐I (0.17 RRT) was isolated using preparative HPLC and characterized by NMR and MS. The other two impurities, Impurity‐II (RRT 0.22) and Impurity‐III (RRT 0.28) could not be isolated, hence they are characterized by HPLC‐hyphenated techniques, LC–NMR and high‐resolution LC–MS. On the basis of the spectral data, the Impurity‐I, Impurity‐II and Impurity‐III were characterized as 1‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐methyl‐4‐oxo‐1,4‐dihydropyridine‐2‐carboxylic acid, 1H‐benzo [d] imidazole‐2‐sulfonic acid and 4‐(3‐methoxy propoxy)‐3‐methyl‐2‐pyridine carboxylic acid, respectively. Copyright © 2009 John Wiley & Sons, Ltd.     

Electrochemical oxidation of C4-vanillin- and C4-isovanillin-1,4-dihydropyridines in aprotic medium: Reactivity towards free radicals

This work reports the electrochemical oxidation of two new synthetic C4-vanillin and -isovanillin-1,4-dihydropyridines in aprotic medium. Its reactivity with alkylperoxyl radicals ABAP-derived at pH 7.4 is also studied. Voltammetry, coulometry, controlled-potential electrolysis, UV–visible spectroscopy and GC–MS techniques were employed to collect data that permitted us to study its oxidation. Effect of TBA-OH addition on the oxidation was electrochemically and spectroscopically followed. In aprotic medium, the oxidation mechanism involves the formation of the pyridine derivative, which was generated by controlled-potential electrolysis (CPE) at 1270 mV and identified by GC–MS technique as the final product of the electrolysis. Spectroelectrochemical experiments also support the formation of the pyridine derivative from the oxidation of both 1,4-dihydropyridines. Direct reactivity of synthesized compounds towards alkylperoxyl radicals ABAP-derived was determined. Results reveal that the inclusion of vanillin radical or its positional isomer, isovanillin in the 4-position of the dihydropyridine ring produced a significant positive effect on the reactivity towards alkylperoxyl radicals, even compared with commercial dihydropyridine drugs with a well-known antioxidant ability. Scavenging mechanism involves the electron-transfer and the formation of a pyridine derivative, which was identified by GC–MS.     

Structural and optical profile of a multifunctionalized 2‐pyridone derivative in a crystal engineering perspective

The supramolecular structural features of organic molecules are very important with regard to their widespread properties in both solids and solutions. Herein, we describe the synthesis of a novel multifunctional 2‐pyridone derivative, namely 6‐(4‐chlorophenyl)‐5‐formyl‐4‐methylsulfanyl‐2‐oxo‐1,2‐dihydropyridine‐3‐carbonitrile, C₁₄H₉ClN₂O₂S, denoted P1 , and its structural features were established through X‐ray crystallography. A Hirshfeld surface analysis followed by a two‐dimensional fingerprint plot analysis was carried out. A frontier molecular orbital investigation and natural bond orbital (NBO) calculations explored the charge‐transfer interactions associated with the molecular system. The optical properties of the 2‐pyridone derivative were elucidated through UV–Vis absorption and emission spectroscopy, indicating a strong blue emissive nature with a colour purity of 82.5%, a short‐lived lifetime and a large Stokes shift. Time‐dependent density functional theory (TD‐DFT) was used to gain some insight into the absorption behaviour and emissive characteristics of P1 .     

Performance of zwitterionic hydrophilic interaction LC for the determination of iodinated X‐ray contrast agents

This study compares the separation performance of a group of iodinated X‐ray contrast media on four different columns. The first three were two stationary phases (SPs) modified with C₁₈ and a polar‐embedded SP (polar amide group bonded to an alkyl chain), all of which worked under RP‐LC mode. The fourth was a zwitterionic sulphoalkylbetaine SP, working under the hydrophilic interaction LC (HILIC) mode. After the optimisation of the different parameters, the zwitterionic column displayed the best separation, which also overcomes the problems encountered when these analytes were separated under RP‐LC. Moreover, when HILIC is coupled to MS/MS, sensitivity is enhanced. However, when sewage samples were analysed by SPE followed by the optimal HILIC–MS/MS, the sensitivity of the method was affected due to the high matrix effect, which had to be solved by dilution of the extract. Finally, the method was preliminarily validated with sewage and the figures of merit were comparable to those of the SPE–RP‐LC–MS/MS.     

Physical Hydrogels of Poly(vinyl alcohol) with Different Syndiotacticity Prepared in the Presence of Lactosilated Chitosan Derivatives

Poly(vinyl alcohol) (PVA) physical hydrogels were prepared by repeated freeze–thawing cycles using aqueous solutions of two PVA samples having different degrees of syndiotacticity, a‐PVA and s‐PVA with 55% and 61% of syndiotactic diads, respectively. The hydrogels were prepared in the presence of different amounts of lactosilated chitosan derivatives (LC) of different molecular weight. The PVA stereoregularity was found to have a dramatic effect on the amount of PVA incorporated into the hydrogels, leading to remarkable differences in the swelling degree and porosity of a‐PVA and s‐PVA hydrogels. A significant amount of LC was retained in the hydrogels after equilibrium swelling. The swelling of the a‐PVA hydrogels was found to increase significantly by increasing the amount of LC while it was only slightly increased in the case of s‐PVA hydrogels. The amount of LC released after equilibrium swelling was lower when chitosan derivatives with higher molecular weights were used. Increased initial concentrations of LC resulted in much higher porosity of the hydrogels. TGA and DSC studies showed that LC is stabilized by the incorporation in the PVA hydrogels. The melting temperature of the crystalline regions of PVA was not significantly influenced by LC. Conversely, the extension of the crystalline domains increased in the presence of LC. The retention of a chitosan derivative bearing β‐D ‐galactose side chain residues makes these hydrogels potentially useful as scaffolds for hepatocytes culture.

Scanning electron micrographs of PVA‐LC hydrogels: (a) a‐PVA; (b) a‐PVA/LC₁₅₀ 80:20; (c) a‐PVA/LC₁₅₀ 50:50.     

A new reverse mode light shutter from silica-dispersed liquid crystals

Nanoparticle dispersions in liquid crystalline materials at low concentrations allow both investigating the formation of defects in liquid crystal (LC) and enhancing the light-scattering properties of LC optical devices. Reverse mode LC dispersions are LC devices, which look like transparent in their OFF state, when no electric field is applied, and opaque in their ON state. In this paper, a new reverse mode device, formed by a dispersion of a LC mixture in a silica nanoparticle crosslinked network, is presented. The morphology and the electro-optical properties of these silica nanoparticle/LC composites were investigated for two different LC mixtures with a negative dielectric anisotropy. The observed transmittances and relaxation times were found to depend strongly on the silica amount and chemical–physical properties of LC used in the sample preparation.     

Preparation and reaction of isomeric formyl-2,1-benzisoxazoles

The novel 4-formyl-2,1-benzisoxazole and 7-formyl-2,1-benzisoxazole were prepared for conversion via the Hantzsch synthesis to 1,4-dihydropyridines. The 4-formyl derivative underwent efficient cyclization to the dihydropyridine while analogous reaction of the 7-formyl compound has proven problematic.     

Syntheses of Diamino-dideoxylyxose Derivatives using Acylnitroso Dienophiles

N-Acylnitroso derivatives 6 which were prepared by in-situ oxidation of the corresponding hydroxamic acids 5 reacted instantaneously and in high yields with dihydropyridine 4 . The Diels-Alder adducts 8 were formed regiospecifically with the acylnitroso dienophiles 6a–c , whereas the dienophiles 6d–f gave mixtures of both regioisomers 7 and 8 . These and some other results [2] were best explained by the FMO theory. The Diels-Alder adducts 7 and 8 gave the corresponding ‘anti’-cis-glycols when reacted with OsO₄/N-methylmorpholine N-oxide. Hydrogenolysis of the N–O bond followed by peracetylation led to the expected aminolyxose derivatives 14 and 16 . A similar sequence, using 4 and the hydroxamic-acid derivative 18 of (+)-D-mandelic acid led, with a poor asymmetric induction, to a mixture of the expected optically active aminolyxose compounds 19A / 19B .     

Light-driven phase transition in a cubic-phase-forming binary system composed of 4'-n-docosyloxy-3'-nitrobiphenyl-4-carboxylic acid and an azobenzene derivative

Binary mixtures were prepared from an azobenzene derivative and a liquid-crystal (LC) compound that exhibits smectic?C (SmC) and bicontinuous cubic (Cub(bi)) LC phases. Reversible switching between the two phases in response to UV-light irradiation was observed. This light-driven SmC-to-Cub(bi) transition is the first example showing the increased dimensionality of molecular ordering with isomerization of azobenzenes (see figure).     

Heart‐cut nano‐LC–CZE–MS for the characterization of proteins on the intact level

Multidimensional separation techniques play an increasingly important role in separation science, especially for the analysis of complex samples such as proteins. The combination of reversed‐phase liquid chromatography in the nanoscale and CZE is especially beneficial due to their nearly orthogonal separation mechanism and well‐suited geometries/dimensions. Here, a heart‐cut nano‐LC–CZE–MS setup was developed utilizing for the first time a mechanical 4‐port valve as LC–CE interface. A model protein mixture containing four different protein species was first separated by nano LC followed by a heart‐cut transfer of individual LC peaks and subsequent CZE–MS analysis. In the CZE dimension, various glycoforms of one protein species were separated. Improved separation capabilities were achieved compared to the 1D methods, which was exemplarily shown for ribonuclease B and its different glycosylated forms. LODs in the lower μg/mL range were determined, which are considerably lower compared to traditional CZE–MS. In addition, this study represents the first application of an LC–CE–MS system for intact protein analysis. The nano‐LC–CZE–MS system is expected to be applicable to various other analytical challenges.     

Thermotropic liquid‐crystalline polymers having five‐membered heterocycles as mesogens, 6. Synthesis,thermotropic liquid‐crystalline and photoluminescent properties of novel semi‐rigid polyesters based on a terphenyl analogue of 1,3,4‐thiadiazole

Novel semi‐rigid thermotropic liquid‐crystalline (LC) polyesters containing terphenyl analogue of 1,3,4‐thiadiazole in the main chain were synthesized by melt polycondensation of a dioxydiundecanol derivative of 2,5‐diphenyl‐1,3,4‐thiadiazole with four aromatic diesters, and their structures were confirmed from FTIR, ¹³C NMR spectra and elemental analyses. Differential scanning calorimetry (DSC) measurements and polarizing microscope observations of textures showed that all the polymers form enantiotropic LC (smectic) phases. UV‐vis and photoluminescence (PL) spectra indicated that polyesters without nitro groups display maximum absorbances arising from 1,3,4‐thiadiazole moiety and blue‐emission maxima, the Stokes shifts being 69.5–79 nm in solution and 54–97 nm in the solid state.     

Cascade reaction of imines with phenylsulfinylallene. X-ray structure of the product and its formation mechanism

The structure of the product derived from the reaction of a dihydropyridine derivative with phenylsulfinylallene has been clarified by a single crystal X-ray analysis and the formation mechanism is discussed on the basis of the reaction-path calculations by semiempirical and ab initio molecular orbital methods.     

Automatic analyzer for highly polar carboxylic acids based on fluorescence derivatization–liquid chromatography

A sensitive, versatile, and reproducible automatic analyzer for highly polar carboxylic acids based on a fluorescence derivatization–liquid chromatography (LC) method was developed. In this method, carboxylic acids were automatically and fluorescently derivatized with 4‐(N,N‐dimethylaminosulfonyl)‐7‐piperazino‐2,1,3‐benzoxadiazole (DBD‐PZ) in the presence of 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium chloride by adopting a pretreatment program installed in an LC autosampler. All of the DBD‐PZ‐carboxylic acid derivatives were separated on the ODS column within 30 min by gradient elution. The peak of DBD‐PZ did not interfere with the separation and the quantification of all the acids with the exception of lactic acid. From the LC‐MS/MS analysis, we confirmed that lactic acid was converted to an oxytriazinyl derivative, which was further modified with a dimethoxy triazine group of 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methylmorpholinium chloride (DMT‐MM). We detected this oxytriazinyl derivative to quantify lactic acid. The detection limits (signal‐to‐noise ratio = 3) for the examined acids ranged from 0.19 to 1.1 µm , which correspond to 95–550 fmol per injection. The intra‐ and inter‐day precisions of typical, highly polar carboxylic acids were all <9.0%. The developed method was successfully applied to the comprehensive analysis of carboxylic acids in various samples, which included fruit juices, red wine and media from cultured tumor cells. Copyright © 2014 John Wiley & Sons, Ltd.     

High-temperature chiral nematic phase in naphthalene and cholesterol derivative liquid crystal: characterisation and dielectric relaxation study

In this article, we report the synthesis of the naphthalene and cholesterol derivative 2-(cholesterol-n-decanoate)-6-(heptyloxy benzoate) naphthalene (2CD6HBN) liquid crystal (LC) having chiral nematic (N*) mesophase. The synthesised mesophase has been characterised using polarising optical microscopy (POM) and differential scanning calorimetric (DSC) study. The presence of the rigid and less polarisable cores causes a higher N*-Iso transition temperature. The relaxation phenomenon of the present LC sample was analysed by the dielectric relaxation spectroscopic study. The dielectric properties, electrical conductivity and the relaxation time were observed as a function of the temperature. The relaxation time follows the first-order exponential decay–type equation. The properties of the LC sample have also been correlated with the structure of the compound.     

Separation and Characterization of Unknown Impurities in Amikacin Sulfate by HPLC–MS n

Nine impurities in amikacin sulfate made in China were separated and identified by HPLC–MSⁿ for the further improvement of official monographs in pharmacopoeias. The mass fragmentation patterns and structural assignment of these impurities were studied. The column was Acchrom Click XIon (250 × 4.6 mm, 5 μm). The mobile phase was 250 m mol L⁻¹ ammonium formate and 1.4 % formic acid aqueous solution–acetonitrile–water (30:48:22). In positive mode, full scan LC–MS was first performed in order to obtain the m/z value of the protonated molecules, LC–MS–MS was then carried out on the compounds of interest on AB SCIEX 4000 Q TRAP™ composite triple quadrupole/linear ion trap tandem mass spectrometer. The complete fragmentation patterns of nine impurities were studied and used to obtain information about the structure of these impurities. The structures of nine impurities in amikacin sulfate were deduced based on the HPLC–MSⁿ data, in which three impurities were novel impurities. Three novel impurities were 1-N-(l-4-amino-2-hydroxybutyryl) derivative of 4-O-(6-AG)DS, 1-N-(l-4-amino-2-hydroxybutyryl) derivative of 6-O-(3-AG)DS and 1-N-(l-4-amino-2-hydroxybutyryl) derivative of kanamycin D.

     

Comparison of analytical approaches for liquid chromatography/mass spectrometry determination of the alcohol biomarker ethyl glucuronide in urine

Official guidelines originating from a European Union directive regulate requirements for analytical methods used to identify chemical compounds in biological matrices. This study compared different liquid chromatography/electropray ionization mass spectrometry (LC/ESI‐MS) and tandem mass spectrometry (LC/ESI‐MS/MS) procedures for accurate determination of the conjugated ethanol metabolite and alcohol biomarker ethyl glucuronide (EtG) in urine, and the value of combined EtG and ethyl sulfate (EtS) measurement. Analysis was carried out on 482 urines following solid‐phase extraction (SPE) sample cleanup or using direct injection of a diluted sample. SPE combined with LC/MS/MS was demonstrated to be the most selective and sensitive method and was chosen as reference method. The EtG results by different methods showed good correlation (r = 0.96–0.98). When comparing five reporting limits for EtG in the range 0.10–1.00 mg/L, the overall agreement with the reference method (frequency of true positives plus true negatives) was 82–97% for direct‐injection LC/MS/MS, 90–97% for SPE‐LC/MS, 86–98% for direct‐injection LC/MS, and 86–98% for direct‐injection LC/MS analysis of EtG and EtS. Most deviations were attributable to uncertainty in quantitation, when the value was close to a cutoff but the respective results were slightly above and below, or vice versa, the critical limit. However, for direct‐injection LC/MS/MS, despite earning 4 identification points, equally many negative results were due to a product ion ratio outside the ±20% deviation accepted by the guidelines. These results indicate that the likelihood of different analytical methods to provide reliable analytical results depends on the reporting limit applied. Copyright © 2010 John Wiley & Sons, Ltd.     

Helical polyacetylene—Origins and synthesis

We present the origins and synthesis of helical polyacetylene (H‐PA) by focusing on its peculiar spiral morphology. Interfacial polymerization of acetylene was carried out in an asymmetric reaction field consisting of chiral nematic liquid crystal (N*‐LC) and Ziegler–Natta catalyst. As the N*‐LC is composed of nematic liquid crystal and a chiral compound such as a binaphthyl derivative with either the R‐ or S‐configuration, the screw directions of the polyacetylene chain and fibril bundle—and even the spiral morphology—are rigorously controlled by the chirality of the selected compound. Interestingly, the screw directions of the fibril and the bundle in H‐PA were found to be opposite to that of N*‐LC. It is worthwhile to emphasize that the hierarchical spiral morphology involving the primary to higher order structure is generated in a synthetic polymer such as polyacetylene by using N*‐LC as an asymmetric polymerization solvent. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 395–406; 2008: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20163