A Transition‐Metal‐Free Synthesis of Multisubstituted Imidazoles

A novel and simple t‐BuOLi/I₂‐mediated synthesis of 1,2,4‐trisubstituted imidazoles was developed without transition‐metal added. The transition‐metal‐free strategy tolerated a range of substrates and provided products in moderate to good yields with 100% regioselectivity.     

Rapid sampling of all‐atom peptides using a library‐based polymer‐growth approach

We adapted existing polymer growth strategies for equilibrium sampling of peptides described by modern atomistic forcefields with a simple uniform dielectric solvent. The main novel feature of our approach is the use of precalculated statistical libraries of molecular fragments. A molecule is sampled by combining fragment configurations—of single residues in this study—which are stored in the libraries. Ensembles generated from the independent libraries are reweighted to conform with the Boltzmann‐factor distribution of the forcefield describing the full molecule. In this way, high‐quality equilibrium sampling of small peptides (4–8 residues) typically requires less than one hour of single‐processor wallclock time and can be significantly faster than Langevin simulations. Furthermore, approximate, clash‐free ensembles can be generated for larger peptides (up to 32 residues in this study) in less than a minute of single‐processor computing. We discuss possible applications of our growth procedure to free energy calculation, fragment assembly protein‐structure prediction protocols, and to “multi‐resolution” sampling. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Preparation of Ionic Liquid‐based Vilsmier Reagent from Novel Multi‐purpose Dimethyl Formamide‐like Ionic Liquid and Its Application

In continuation of research to explore the applied potential of DMF‐like ionic liquid, the ionic liquid version of N,N‐dimethyliminiumchloride (Vilsmier reagent) has been synthesized from DMF‐like ionic liquid and tested effectively for its capacity to achieve more useful organic transformations. The results show that DMF‐like ionic liquid is world's first task specific ionic liquid which has catalyzed numerous diverse type of reaction and is multipurpose in its application. Thus a new term for this DMF‐like ionic liquid has been coined that is DMF‐like "multipurpose" ionic liquid.     

Screening and rank ordering of reversible mechanism‐based inhibitors of Hepatitis C virus NS3 protease using electrospray ionization mass spectrometry

An affinity‐selection study using size exclusion chromatography (SEC) combined with off‐line electrospray ionization mass spectrometry (ESI‐MS) was performed on libraries of peptidic α‐ketoamide inhibitors directed against the hepatitis C virus (HCV) NS3 protease. A limiting amount of HCV NS3 protease (25 µM ) was incubated with equimolar amounts (100 µM ) of 49 reversible mechanism‐based ketoamide inhibitors, previously grouped into seven sets to ensure clearly distinguishable mass differences of the enzyme‐inhibitor complexes (>10 Da). The unbound compounds were separated rapidly from the protease and the protease‐inhibitor complexes by SEC spin columns. The eluate of the SEC was immediately analyzed by direct‐infusion ESI‐MS. An enzyme‐inhibitor complex, with a molecular mass corresponding to the NS3 protease binding to the preferred inhibitor, SCH212986, was the only molecular species detected. By increasing the molar ratio of HCV NS3 protease to inhibitors to 1:2 while keeping the inhibitors' concentration constant, the complex of the second most tightly bound inhibitor, SCH215426, was also identified. Although the potencies of these inhibitors were virtually un‐measurable by kinetic assays, a rank order of CVS4441 > SCH212986 > SCH215426 was deduced for their inhibition potencies by direct competition experiment with CVS4441 ( M ). As discussed in the article, through judicious application of this strategy, even large libraries of fairly weak, reversible and slow‐binding inhibitors could be rapidly screened and rank ordered to provide critical initial structure‐activity insights. Copyright © 2011 John Wiley & Sons, Ltd.     

Liquid‐crystalline azobenzene‐containing ferrocene‐based polymers: study on synthesis and properties of main‐chain ferrocene‐based polyesters with azobenzene in the side chain

Ferrocene‐based polymers are characterized by their electrochemical activity, good redox properties, thermal, photochemical stability, and liquid crystallinity, and thus they have various applications in different fields. A comprehensive investigation on the synthesis and properties of three novel main‐chain ferrocene‐based polyesters with azobenzene in the side chain (MFPAS) was carried out. The main‐chain ferrocene‐based polyester, poly(N‐phenyldiethanolamine 1,1′‐ferrocene dicarboxylate (PPFD), was synthesized via the solution polycondensation reaction of 1,1′‐ferrocenedicarbonyl chloride with phenyldiethanolamine (PDE). The novel MFPAS were synthesized via the post‐polymerization azo‐coupling reaction of PPFD with three different 4‐substituted anilines including 4‐nitroaniline, 4‐aminobenzoic acid, and 4‐aminobenzonitrile to produce 4‐nitrophenylazo‐functionalized‐PPFD (PPFD‐NT), 4‐carboxyphenylazo‐functionalized‐PPFD (PPFD‐CA), and 4‐cyanophenylazo‐functionalized‐PPFD (PPFD‐CN), respectively. All the synthesized polymers were characterized by ¹H NMR spectroscopy, Fourier transform infrared spectroscopy, and UV–visible spectroscopy. In addition, powder X‐ray diffraction patterns were measured for the synthesized polymers. The photoisomerization of the MFPAS was studied. The thermal properties of the MFPAS were studied using thermogravimetric analysis and differential scanning calorimetry. PPFD‐CA and PPFD‐CN were found to be more thermally stable than PPFD‐NT. Finally, the liquid‐crystalline properties of PPFD and the MFPAS were examined using polarized optical microscope. It was found that all the polymers possessed nematic phases and exhibited textures with schlieren disclinations. Copyright © 2012 John Wiley & Sons, Ltd.     

Bio‐based comb‐like copolymers derived from alkyl 10‐undecenoates and maleic anhydride

In this article, 10‐undecenoic acid, based on castor oil, was used a raw material for the synthesis of alternating copolymers. ω‐Unsaturated fatty esters as alkyl 10‐undecenoates were prepared by the esterification reaction of 10‐undecenoic acid with alkyl alcohol. A series of comb‐like copolymers were synthesized by free radical polymerization from maleic anhydride and alkyl 10‐undecenoates copolymers with different length of alkyl side chains in a toluene solution. These copolymers were investigated by ¹H and ¹³C nuclear magnetic resonance, Fourier transform infrared spectroscopy, gel permeation chromatography, thermogravimetric analysis, differential scanning calorimetry (DSC). The copolymers were obtained in a low molecular weight in a range 3370–12,240 g mol⁻¹ and their structural characterization indicated the formation of alternating copolymers. DSC characterization revealed that these comb‐like copolymers showed amorphous to semicrystalline behavior by increasing the length of side chains. The bio‐based comb‐like copolymers allow for the development of new polymeric materials for several applications. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1039–1045     

Comparison of HPLC enantioseparation of substituted binaphthyls on CD‐, polysaccharide‐ and synthetic polymer‐based chiral stationary phases

Retention and enantioseparation behavior of ten 2,2′‐disubstituted or 2,3,2′‐trisubstituted 1,1′‐binaphthyls and 8,3′‐disubstituted 1,2′‐binaphthyls, which are used as catalysts in asymmetric synthesis, was investigated on eight chiral stationary phases (CSPs) based on β‐CD, polysaccharides (tris(3,5‐dimethylphenylcarbamate) cellulose or amylose CSPs) and new synthetic polymers (trans‐1,2‐diamino‐cyclohexane, trans‐1,2‐diphenylethylenediamine and trans‐9,10‐dihydro‐9,10‐ethanoanthracene‐(11S,12S)‐11,12‐dicarboxylic acid CSPs). Normal‐, reversed‐phase and polar‐organic separation modes were employed. The effect of the mobile phase composition was examined. The enantiomeric separation of binaphthyl derivatives, which possess quite similar structures, was possible in different enantioselective environments. The substituents and their positions on the binaphthyl skeleton affect their properties and, as a consequence, the separation system suitable for their enantioseparation. In general, the presence of ionizable groups on the binaphthyl skeleton, substitution with non‐identical groups and a chiral axis in the 1,2′ position had the greatest impact on the enantiomeric discrimination. The 8,3′‐disubstituted 1,2′‐binaphthyl derivatives were the most easily separated compounds in several separation systems. From all the chiral stationary phases tested, cellulose‐based columns were shown to be the most convenient for enantioseparation of the studied analytes. However, the polymeric CSPs with their complementary behavior provided good enantioselective environments for some derivatives that could be hardly separated in any other chromatographic system.     

Iterative In Situ Click Chemistry Creates Antibody‐like Protein‐Capture Agents

Special agents for protein capture : Iterative in situ click chemistry (see scheme for the tertiary ligand screen) and the one‐bead–one‐compound method for the creation of a peptide library enable the fragment‐based assembly of selective high‐affinity protein‐capture agents. The resulting ligands are water‐soluble and stable chemically, biochemically, and thermally. They can be produced in gram quantities through copper(I)‐catalyzed cycloaddition.

     

Computational study of pH‐responsive di‐lanthanide complexes

Lanthanide complexes have found extensive use as luminescent probes for biological and medical investigations. Recently, a di‐europium complex that exhibits pH‐dependent luminescence‐decay was reported, and the ligand in that complex includes a large number of ionizable sites. To better understand the pH‐dependence of luminescence‐decay of this complex, the pK _a's of all tautomers of the di‐Lu³⁺ version of this complex were calculated computationally. The calculated Boltzmann‐averaged pK _a's of the complex are 5.85, ?0.21, and ?1.47 for the di‐Lu³⁺ complex in its first, second, and third protonation states, respectively. These pK _a values across protonation states indicate that changes in luminescence‐decay rate at physiologically relevant pH may be related to first protonation event of the complex exclusively.     

Interaction study of acetylcholinestrase inhibitors on pharmacokinetics of memantine in rat plasma by HPLC‐fluorescence method

The present study aims to investigate the possibility of interaction of donepezil (DP) and galantamine (GAL) as acetylcholinestrase inhibitors, on memantine (MT) hydrochloride in rat plasma by HPLC‐fluorescence detection. The separation of MT was achieved within 12 min without interference of DP and GAL on the chromatogram. MT levels in rat plasma with a single administration of MT (2.5 mg/kg, i.p.) and those with a co‐administration of DP (5.0 mg/kg, i.p.) and GAL (3 mg/kg, i.p.) were monitored. MT concentrations determined in rat plasma ranged from 10.0 to 245.6 ng/mL. Significant difference was observed in the behavior of MT with a co‐administration of DP, while no significant difference was observed with a co‐administration of GAL. Copyright © 2013 John Wiley & Sons, Ltd.     

Bioactivity‐based ultra‐performance liquid chromatography‐coupled quadrupole time‐of‐flight mass spectrometry for NF‐κB inhibitors identification in Chinese Medicinal Preparation Bufei Granule

Traditional Chinese medicine (TCM) preparations have become effective treatments for many diseases. However, their active ingredients are still uncertain and difficult to identify. In this study, we propose a strategy that integrates ultra‐performance liquid chromatography/quadrupole‐time‐of‐flight mass spectrometry (UPLC/Q‐TOF‐MS) and bioactive (NF‐κB inhibitor) luciferase reporter assay systems for the rapid determination of various anti‐inflammatory compounds of TCM preparations. In this way, Bufei Granule (BFG), a TCM preparation used for the clinical therapy of asthma, was analyzed by the two ways of component identification and activity detection. Potential anti‐inflammatory constituents were screened by NF‐κB activity assay systems and simultaneously identified according to the mass spectrometry data. Three structural types of NF‐κB inhibitors (caffeic acid derivatives, flavonoids and Pentacyclic triterpenes) were characterized. Further cytokine detection confirmed the anti‐inflammatory effects of the potential NF‐κB inhibitors. Compared with conventional chromatographic separation and inhibitory activity detection, integrating UPLC/Q‐TOF‐MS identification and virtual validation was more convenient and more reliable. This strategy clearly demonstrates that MS data‐based fingerprinting is a meaningful tool not only in identifying constituents in complex matrix but also in directly screening for powerful trace ingredients in TCM preparations. Copyright © 2016 John Wiley & Sons, Ltd.     

Development of a fast liquid chromatography/mass spectrometry screening method for angiotensin‐converting enzyme (ACE) inhibitors in complex natural mixtures like snake venom

A new robust high‐performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI‐MS)‐based screening method for angiotensin‐converting enzyme (ACE)‐inhibiting substances in crude samples is described. The ACE assay is carried out in a typical offline setup by incubation of the samples with ACE and angiotensin I (AI), followed by stopping the reaction with acetonitrile containing val⁵‐AI serving as internal standard (I.S.). AI and the product angiotensin II (AII) are extracted from the incubation mixture by turbulent‐flow chromatography (TFC) applied in backflush mode as online solid‐phase extraction and are directly quantified by ESI(+)‐MS. The presence of ACE inhibitors (ACEi) is detected by an increase in AI signal intensity and a corresponding decrease of AII signal, as compared to the blank assay. The overall time of analysis of the TFC/ESI‐MS method was 5 min, thus making the described setup suitable for a rapid screening method. The assay was validated using a known ACE inhibitor and the IC₅₀ values found were in good accordance with a common HPLC/UV method and literature data. The method was successfully applied for the screening of size‐exclusion chromatography fractions of the venom of the pitviper Bothrops moojeni. Three of 18 analyzed fractions inhibited ACE, due to peptides present as components of this snake venom. These compounds were extracted from the two most‐active fractions by means of TFC and isolated by means of HPLC. Three peptides with ACE inhibitory activity were characterized and their structures were elucidated with ESI‐MS/MS‐based de novo sequencing to be ZKWPPGKVPP, ZKWPRPGPEIPP and ZNWPRPGPEIPP, respectively (Z = pyroglutamic acid). Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis,crystal structure and activity evaluation of novel 3,4‐dihydro‐1‐benzoxepin‐5(2H)‐one derivatives as protein–tyrosine kinase (PTK) inhibitors

Four new 3,4‐dihydro‐1‐benzoxepin‐5(2H )‐one derivatives, namely (E )‐4‐(5‐bromo‐2‐hydroxybenzylidene)‐6,8‐dimethoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 7 ), (E )‐4‐[(E )‐3‐(5‐bromo‐2‐hydroxyphenyl)allylidene]‐6,8‐dimethoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 8 ), (E )‐4‐(5‐bromo‐2‐hydroxybenzylidene)‐6‐hydroxy‐8‐methoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, C₁₈H₁₅BrO₅, ( 9 ), and (E )‐4‐[(E )‐3‐(5‐bromo‐2‐hydroxyphenyl)allylidene]‐6‐hydroxy‐8‐methoxy‐3,4‐dihydrobenzo[b ]oxepin‐5(2H )‐one, ( 10 ), have been synthesized and characterized by FT–IR, NMR and MS. The structure of ( 9 ) was confirmed by single‐crystal X‐ray diffraction. Crystal structure analysis shows that molecules of ( 9 ) are connected into a one‐dimensional chain in the [010] direction through classical hydrogen bonds and these chains are further extended into a three‐dimensional network via C—H…O interactions. The inhibitory activities of these compounds against protein–tyrosine kinases (PTKs) show that 6‐hydroxy‐substituted compounds ( 9 ) and ( 10 ) are more effective for inhibiting ErbB1 and ErbB2 than are 6‐methoxy‐substituted compounds ( 7 ) and ( 8 ). This may be because ( 9 ) and ( 10 ) could effectively bind to the active pockets of the protein through intermolecular interactions.     

Synthesis of sugar‐based macromolecules via sono‐ATRP in miniemulsion

Ultrasound‐mediated atom transfer radical polymerization (sono‐ATRP) in miniemulsion media is used for the first time for the preparation of complex macromolecular architectures by a facile two‐step synthetic route. Initially, esterification reaction of sucrose or lactulose with α‐bromoisobutyryl bromide (BriBBr) is conducted to receive multifunctional ATRP macroinitiators with 8 initiation sites, followed by polymerization of n‐butyl acrylate (BA) forming arms of the star‐like polymers. The brominated lactulose‐based molecule was examined as an ATRP initiator by determining the activation rate constant (k_a) of the catalytic process in the presence of a copper(II) bromide/tris(2‐pyridylmethyl)amine (Cu^IIBr₂/TPMA) catalyst in both organic solvent and for the first time in miniemulsion media, resulting in k_a = (1.03 ± 0.01) × 10⁴ M^?1 s^?1 and k_a = (1.16 ± 0.56) × 10³ M^?1 s^?1, respectively. Star‐like macromolecules with a sucrose or lactulose core and poly(n‐butyl acrylate) (PBA) arms were successfully received using different catalyst concentration. Linear kinetics and a well‐defined structure of synthesized polymers reflected by narrow molecular weight distribution (M_w/M_n = 1.46) indicated 105 ppm wt of catalyst loading as concentration to maintain controlled manner of polymerization process. ¹H NMR analysis confirms the formation of new sugar‐inspired star‐shaped polymers.     

Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate‐based cholera toxin inhibitors

Developing tools for the study of protein carbohydrate interactions is an important goal in glycobiology. Cholera toxin inhibition is an interesting target in this context, as its inhibition may help to fight against cholera. For the study of novel ligands an affinity capillary electrophoresis (ACE) method was optimized and applied. The method uses unlabeled cholera toxin B‐subunit (CTB) and unlabeled carbohydrate ligands based on ganglioside GM1‐oligosaccharides (GM1os). In an optimized method at pH 4, adsorption of the protein to the capillary walls was prevented by a polybrene‐dextran sulfate‐polybrene coating. Different concentrations of the ligands were added to the BGE. CTB binding was observed by a mobility shift that could be used for dissociation constant (K_d) determination. The K_d values of two GM1 derivatives differed by close to an order of magnitude (600 ± 20 nM and 90 ± 50 nM) which was in good agreement with the differences in their reported nanomolar IC₅₀ values of an ELISA‐type assay. Moreover, the selectivity of GM1os towards CTB was demonstrated using Influenza hemagglutinin (H5) as a binding competitor. The developed method can be an important platform for preclinical development of drugs targeting pathogen‐induced secretory diarrhea.     

Calcification resistance of polyisobutylene and polyisobutylene‐based materials

Calcification of implanted biomaterials is highly undesirable and limits clinical applicability. Experiments were carried out to assess the calcification resistance of polyisobutylene (PIB), PIB‐based polyurethane (PIB‐PU), PIB‐PU reinforced with (CH₃)₃N⁺CH₂CH₂CH₂NH₂ I^?‐modified montmorillonite (PIB‐PU/nc), PIB‐based polyurethane urea (PIB‐PUU), PIB‐PU containing S atoms (PIB_S‐PU), PIB_S‐PU reinforced with (CH₃)₃N⁺CH₂CH₂CH₂NH₂ I^?‐modified montmorillonite (PIB_S‐PU/nc), and poly(isobutylene‐b‐styrene‐b‐isobutylene) (SIBS), relative to that of a clinically widely implanted polydimethylsiloxane (PDMS)–based PU, Elast‐Eon (the “control”). Samples were incubated in simulated body fluid for 28 days at 37°C, and the extent of surface calcification was analyzed by scanning electron microscopy (SEM), atomic force microscopy (AFM), energy‐dispersive X‐ray spectroscopy (EDX), X‐ray photoelectron spectroscopy (XPS), and Fourier‐transform‐infrared (FT‐IR) spectroscopy. Whereas the PDMS‐based PU showed extensive calcification, PIB and PIB‐PU containing 72.5% PIB, ie, a polyurethane whose surface is covered with PIB, were free of calcification. PIB_S‐PU and PIB‐PUU, ie, polyurethanes that contain S or urea groups, respectively, were slightly calcified. The amine‐modified montmorillonite‐reinforcing agent reduced the extent of calcification. SIBS was found slightly calcified. Evidently, PIB and materials fully coated with PIB are calcification resistant.     

Bio‐based high‐performance waterborne hyperbranched polyurethane thermoset

Tannic‐acid‐based low volatile organic compound‐containing waterborne hyperbranched polyurethane was prepared. In order to improve the performance, it was modified in an aqueous medium using a glycerol‐based hyperbranched epoxy and vegetable‐oil‐based poly(amido amine) at different wt%. The combined system was cross‐linked by heating at 100°C for 45 min. Fourier transform infrared spectroscopy and swelling study were used to confirm the curing. A dose‐dependent improvement of properties was witnessed for the thermoset. Thermoset with 30 wt% epoxy showed excellent improvements in mechanical properties like tensile strength (~3.4 fold), scratch hardness (~2 fold), impact resistance (~1.3 fold), and toughness (~1.7 fold). Thermogravimetric analysis revealed enhancement of thermal properties (maximum 70°C increment of degradation temperature and 8°C increment of T_g). The modified system showed better chemical and water resistance compared with the neat polyurethane. Biodegradation study was carried out by broth culture method using Pseudomonas aeruginosa as the test organism. An adequate biodegradation was witnessed, as evidenced by weight loss profile, bacterial growth curve, and scanning electron microscope images. The work showed the way to develop environmentally benign waterborne polyurethane as a high‐performance material by incorporating a reactive modifier into the polymer network. Use of benign solvent and bio‐based materials as well as profound biodegradability justified eco‐friendliness and sustainability of the modified system. Copyright © 2015 John Wiley & Sons, Ltd.     

Chiral high‐performance liquid and supercritical fluid chromatographic enantioseparations of limonene‐based bicyclic aminoalcohols and aminodiols on polysaccharide‐based chiral stationary phases

Enantioseparation of limonene‐based bicyclic 1,3‐aminoalcohols and 1,3,5‐ and 1,3,6‐aminodiols was performed by normal‐phase high‐performance liquid chromatographic and supercritical fluid chromatographic (SFC) methods on polysaccharide‐based chiral stationary phases. The effects of the composition of the mobile phase, the column temperature and the structures of the analytes and chiral selectors on retention and selectivity were investigated by normal‐phase LC and SFC technique. Thermodynamic parameters derived from selectivity–temperature‐dependence studies were found to be dependent on the chromatographic method applied, the nature of the chiral selector and the structural details of the analytes. Enantiorecognition in most cases was enthalpically driven but an unusual temperature behavior was also observed: decreased retention times were accompanied by improved separation factors with increasing temperature, i.e. some entropically driven separations were also observed. The elution sequence was determined in all cases. The separation of the stereoisomers was optimized in both chromatographic modalities.