Modeling of ligands for native and chiral modified NMDA receptor NR1-binding core

Native and chiral modified (with non-enzymatic Asn racemization) NR1-ligand binding core of NMDA-receptor was modeled by means of molecular dynamic ligand modeling. Results demonstrated that Gly, D-Ser, D-Asn and D-Thr are ligands of the NR1-binding core of native NMDA-receptor, whereas the chiral modified NR1-binding core is characterized by the aliphatic non-polar amino acids D-Ala, D-Leu, D-Ile and D-Pro as ligands. These amino acids can be considered as effective ligands of the NMDA-receptor NR1-binding core in age-related pathology.     

Structure‐retention relationship for enantioseparation of selected fluoroquinolones

Fluoroquinolones are popular class of antibiotics with distinct chemical functionality. Most of them are ampholytes with one chiral center. Stereogeneic center is located either in the side ring of Gatifloxacin (GFLX) or in the quinolone core of Ofloxacin (OFLX). These two amphoteric fluoroquinolones have terminal amino groups in common. The unusual Nadifloxacin (NFLX) is an acidic fluoroquinolone with a core chiral center. Owing to chirality and functionality differences among GFLX, OFLX, and NFLX, we mapped these enantiomers onto structure‐retention relationship. Amount of acetic acid modifier was studied in screened mobile phase and cellulose tris(3‐chloro‐4‐methyl phenyl carbamate) (Lux cellulose‐2) stationary phase. Experimental design of acetic acid% along with column temperature have been applied. Resolution and enantioselectivity have been related to structural features of the studied enantiomers. High amount of acid (0.4%) was optimum for the separation of either side chirality with a proximate amino group (GFLX) or core chirality without basic functionality (NFLX), while low amount (0.2%) is optimum for core chiral center with distal amino group (OFLX). Temperature has no significant effect on resolution and retention of enantiomers except for OFLX. Enantio‐retention explains possible chiral selective and nonselective interactions. The proposed methods have been validated for pharmaceutical analyses.     

Synthesis and chiroptical properties of chiral azoaromatic dendrimers with a C3‐symmetrical core

New chiral azoaromatic dendrimeric systems have been synthesized starting from 1,3,5‐benzenetricarbonyl trichloride as the core molecule. The simultaneous presence of the (S)‐3‐hydroxy pyrrolidinyl ring as the optically active moiety and the azobenzene donor‐acceptor conjugated system as the photochromic group with permanent dipole moment, makes these systems potentially interesting as materials for advanced applications in nanotechnologies. All the compounds obtained have been characterized with particular attention to the effects induced by changing the electron‐withdrawing group in the chromophoric moiety and to their optical activity. A strong nonlinear enhancement of chiroptical properties related to the number of chiral units linked to the symmetrical core is observed in these derivatives, which indicates the presence of conformationally chiral substructures. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Chiral separation based on immobilized intact and fragmented cellobiohydrolase II (CBH II): A comparison with cellobiohydrolase I (CBH I)

Intact and fragmented cellobiohydrolase II (CBH II) were immobilized to silica and used as chiral stationary phases (CSPs) for liquid chromatographic separations of enantiomers. Both acidic and basic chiral compounds could be resolved into their enantiomers on these phases. The enantioselectivities obtained on intact CBH II and its core were almost equivalent. Comparisons were also made with CBH I silica. It was found that the new materials show quite different chiral and chromatographic properties. The enzymatic activity of the CBH II in free solution was influenced by alprenolol and mexiletine, both separated on the corresponding CSP. It indicates that the sites for catalysis and for chiral recognition overlap. © 1995 Wiley-Liss, Inc.     

Synthesis and liquid crystallinity of dendronized carbohydrate liquid crystal

A dendronized carbohydrate thermotropic liquid crystal was synthesized by attaching wedge-shaped mesogens onto a carbohydrate core. These molecules self-organize into chiral columnar hexagonal mesophase with each column slice (4.5 Å thicknesses) filled with average of two molecules. The supramolecular model was further optimized by molecular dynamics simulation. Moreover, chirality successfully expressed in columnar hexagonal mesophase by dendronized carbohydrate molecules may provide inspiration in searching for chiral mesophase of carbohydrate liquid crystals.     

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids

The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane β-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N-protected derivatives of all four stereoisomers of Boc-2-aminocyclobutanecarboxylic acid.     

Chiral liquid-crystalline side chain polymers by enantioselective modification of prochiral parent polymers

The preparation is reported of two side chain polyacrylate samples 1a , b containing a sulfide group linked to the mesogenic core. By oxidation with a preferentially chiral oxaziridine, samples 1a , b were chemoselectively and enantioselectively converted to the corresponding sulfoxide containing polymers 2a , b with an estimated 20% asymmetric induction. The mesophasic behaviour of the parent and oxidized polymer samples is analyzed by thermal and optical techniques. The modification of the prochiral sulfide groups into chiral sulfoxide groups slightly depresses the propensity of the resulting polymers to give stable and persistent mesophases.     

Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding

The crystal structure of an inactive chiral analogue of insulin containing nonstandard substitution allo-Ile(A2) is described at 2.0 A resolution. In native insulin, the invariant Ile(A2) side chain anchors the N-terminal alpha-helix of the A-chain to the hydrophobic core. The structure of the variant protein was determined by molecular replacement as a T(3)R(3) zinc hexamer. Whereas respective T- and R-state main-chain structures are similar to those of native insulin (main-chain root-mean-square deviations (RMSD) of 0.45 and 0.54 A, respectively), differences in core packing are observed near the variant side chain. The R-state core resembles that of the native R-state with a local inversion of A2 orientation (core side chain RMSD 0.75 A excluding A2); in the T-state, allo-Ile(A2) exhibits an altered conformation in association with the reorganization of the surrounding side chains (RMSD 0.98 A). Surprisingly, the core of the R-state is similar to that observed in solution nuclear magnetic resonance (NMR) studies of an engineered T-like monomer containing the same chiral substitution (allo-Ile(A2)-DKP-insulin; Xu, B., Hua, Q. X., Nakagawa, S. H., Jia, W., Chu, Y. C., Katsoyannis, P. G., and Weiss, M. A. (2002) J. Mol. Biol. 316, 435-441). Simulation of NOESY spectra based on crystallographic protomers enables the analysis of similarities and differences in solution. The different responses of the T- and R-state cores to chiral perturbation illustrates both their intrinsic plasticity and constraints imposed by hexamer assembly. Although variant T- and R-protomers retain nativelike protein surfaces, the receptor-binding activity of allo-Ile(A2)-insulin is low (2% relative to native insulin). This seeming paradox suggests that insulin undergoes a change in conformation to expose Ile(A2) at the hormone-receptor interface.     

Evaluation of the Edman degradation product of vancomycin bonded to core‐shell particles as a new HPLC chiral stationary phase

A modified macrocyclic glycopeptide‐based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide‐based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide‐based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core‐shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography‐mass spectrometry with EDP was performed in approximately 3 minutes. Other highlights include simultaneous liquid chromatography separations of rac‐amphetamine and rac‐methamphetamine with VancoShell, rac‐pseudoephedrine and rac‐ephedrine with NicoShell, and rac‐dichlorprop and rac‐haloxyfop with TeicoShell.     

Synthesis of chiral carbocyclic ribonucleotides.

The carbocyclic analogs of CMP, UMP, GMP, IMP, and ribo-TMP, of the same absolute configuration as the naturally occurring beta-D-ribofuranose-based ribonucleoside monophosphates, have been synthesized. The synthetic route employed Mitsunobu coupling of the heterocycles, appropriately protected where necessary, with a differentially protected, chiral carbocyclic core.     

Synthesis of Chiral Carbocyclic Ribonucleotides

Abstract

The carbocyclic analogs of CMP, UMP, GMP, IMP, and ribo-TMP, of the same absolute configuration as the naturally occurring β- D-ribofuranose-based ribonucleoside monophosphates, have been synthesized. The synthetic route employed Mitsunobu coupling of the heterocycles, appropriately protected where necessary, with a differentially protected, chiral carbocyclic core.     

Synthesis and antibacterial activities of chiral 1,3-oxazinan-2-one derivatives

We report here the design, synthesis, and antibacterial activities of novel classes of compounds containing chiral 1,3-oxazinan-2-ones and oxazolidinones as the basic core structures. These compounds are tertiary amines containing the core structures and two aryl substituents. Several of these molecules exhibit potent antibacterial activities against the tested Gram-positive bacteria, including Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis. These compounds represent new structure scaffolds and can be further optimized to give new antibacterial agents with structures significantly different from those of existing classes of antibiotics.     

Chiral mutagenesis of insulin's hidden receptor-binding surface: structure of an allo-isoleucine(A2) analogue

The hydrophobic core of vertebrate insulins contains an invariant isoleucine residue at position A2. Lack of variation may reflect this side-chain's dual contribution to structure and function: Ile(A2) is proposed both to stabilize the A1-A8 alpha-helix and to contribute to a "hidden" functional surface exposed on receptor binding. Substitution of Ile(A2) by alanine results in segmental unfolding of the A1-A8 alpha-helix, lower thermodynamic stability and impaired receptor binding. Such a spectrum of perturbations, although of biophysical interest, confounds interpretation of structure-activity relationships. To investigate the specific contribution of Ile(A2) to insulin's functional surface, we have employed non-standard mutagenesis: inversion of side-chain chirality in engineered monomer allo-Ile(A2)-DKP-insulin. Although the analogue retains native structure and stability, its affinity for the insulin receptor is impaired by 50-fold. Thus, whereas insulin's core readily accommodates allo-isoleucine at A2, its activity is exquisitely sensitive to chiral inversion. We propose that the Ile(A2) side-chain inserts within a chiral pocket of the receptor as part of insulin's hidden functional surface.     

Natural-product-like chiral derivatives by solid-phase synthesis

In this genomics and proteomics age, highly functionalized natural products or natural-product-like compounds are likely to play important roles in understanding the functions of emerging biological targets because they serve as small-molecule chemical probes in modulating a target's specific actions (i.e. activation or deactivation). Development of stereoselective reaction-derived methods on solid phase provides a means of obtaining functionalized chiral core structures that may be used for high-throughout syntheses.     

Twisted paddlewheel rhodium complexes: Contribution of central and axial chirality to ECD,VCD, and NMR spectra

Dirhodium complexes bearing N-substituted chiral amino acid ligands are investigated. These complexes have an unusual twisted paddlewheel structure, showing inherent chirality. We would like to demonstrate that parallel application of chiroptical spectroscopic methods (ECD and VCD) and NMR spectroscopy combined with quantum chemical calculations constitutes a powerful tool to determine the configuration of the complexes unequivocally. Two chiroptical methods are needed to determine the absolute configuration: ECD for the coordinated nitrogen atom and VCD for the rhodium core. A quick to use NMR method is also presented: Upon the coordination of small molecules in the axial position, the relative configuration of both the rhodium core and the nitrogen atom can be determined simultaneously by studying spatial proximities provided by 1D NOE spectra.     

Mono- and bis-quinidine organocatalysts in the asymmetric methanolysis of cis-1,2,3,6-tetrahydrophthalic anhydride: a conformational and mechanistic NMR study

The enantioselective organocatalytic methanolysis of cis-1,2,3,6-tetrahydrophthalic anhydride mediated by quinidine derivatives with pyridazine or anthraquinone core was investigated, carrying out a detailed nuclear magnetic resonance study of the conformational preferences of the alkaloid catalysts in the pure solvent and in the presence of the reaction substrates and products. No significant interaction between the meso-anhydride and the alkaloid derivatives was detected. In contrast, evidence for a considerable influence of the alcohol reactant on the conformational state of some of the chiral organocatalysts could be obtained, which lends support to the hypothesis of general-base catalysis mechanism, as opposed to the nuclephilic one. The catalytic properties of the studied derivatives showed no obvious correlation with their conformational prevalence in the resting state, suggesting that the alkaloid 9-O substituent should have a more active role than merely enforcing the chiral fragments to adopt a preferential reactive conformation. A strong enantioselective interaction between the enantiomers of the hemiester product and the alkaloid derivatives was also observed, leading to the conclusion that in the actual reaction conditions a relatively large fraction of the latter is in the protonated form.     

Determination of the absolute configuration of the glucosinolate methyl sulfoxide group reveals a stereospecific biosynthesis of the side chain

Glucosinolates are plant metabolites containing an anionic nitrogeneous thioglucosidic core structure and a structurally diverse amino acid-derived side chain, which after hydrolysis by thioglucohydrolases (myrosinases) afford biological active degradation products such as nitriles and isothiocyanates. Structural diversity in glucosinolates is partially due to enzymatic modifications occurring on the preformed core structure, like the recently described oxidation of sulfides to sulfoxides catalyzed by a flavin monooxygenase identified in Arabidopsis thaliana. The enzyme product, 4-methylsulfinylbutylglucosinolate, bears a chiral sulfoxide group in its side chain. We have analyzed the epimeric purity of 4-methylsulfinylbutylglucosinolate by NMR methods using a chiral lanthanide shift reagent. The absolute configuration of the sulfoxide group has been established by comparing the ¹H NMR spectra of the two sulfoximine diastereomers of natural 4-methylsulfinylbutylglucosinolate. According to our data, 4-methylsulfinylbutylglucosinolate isolated from broccoli and A. thaliana is a pure epimer and its sulfoxide group has the R_S configuration. The product of the A. thaliana flavin monooxygenase has these same properties demonstrating that the enzyme is stereospecific and supporting its involvement in glucosinolate side chain formation.     

Synthesis and antibacterial activity of some novel chiral fluorophoric biscyclic macrocycles

Synthesis of chiral permanent fluorophoric biscyclic macrocycles incorporating anthraquinone and (S)-BINOL core is described. Interestingly, the biscyclic macrocycle 1 exhibited remarkable antibacterial activity against most of the pathogenic bacteria in the tested concentrations as compared to the other three compounds 2, 14 and 17 as well as the test control, tetracycline. Further biscyclophanes 1 and 2 exhibited permanent fluorescence sensing property even under highly acidic conditions.     

Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation.     

Hassallidin B--second antifungal member of the Hassallidin family

The cyanobacterium Hassallia sp. produces a family of four compounds which exhibit a broad spectrum of antifungal activities. So far only one of these members has been isolated and its structure elucidated. In this study, we present a second member of this group. Mass spectrometry, one- and two-dimensional NMR and chiral GC-MS analysis revealed the same peptidic and fatty acid core for hassallidin B as the first member hassallidin A with an additional carbohydrate unit, a rhamnose attached to the 3-hydroxyl group of the C(14)-acyl side chain. The antifungal potential of hassallidin B is nearly identical to that of hassallidin A.