Molecular recognition and biological application of modified β-cyclodextrins

The molecular recognition based on cyclodextrins(CDs) has become a focus of interest in modern supramolecular chemistry.CDs are known to encapsulate various ions and organic/inorganic molecules in their hydrophobic cavities and form stable inclusion complexes through cooperative noncovalent interactions. During the past few decades, a large variety of modified CDs have been elaborately designed and synthesized, which significantly promotes our molecular-level understanding of the structure–function relationship in many supramolecular systems. Through the accurate analysis on the molecular binding behaviors, one can create a library of CD-based nanoassemblies with controlled physicochemical properties. In this review, we will focus on the stability constant-directed molecular recognition and the biological activities of β-CDs toward some representative bioactive substrates, including metal ions, steroids, porphyrins, amino acids and oligopeptides, as well as drug molecules, with the final goal of promoting their practical applications in the biomedical field.     

Synthesis of molecularly imprinted polymer of βcyclodextrin for the efficient recognition of cholesterol

Polymeric receptors for cholesterol were synthesized by crosslinking β-cyclodextrin (β-CyD) with hexamethylene diisocyanate or toluene 2,4-diisocyanate in dimethyl sulfoxide (DMSO) in the presence of cholesterol as the template. Non-imprinted β-CyD polymers were much poorer in the cholesterol adsorption. When β-CyD was cross-linked by epichlorohydrin in aqueous alkaline solutions (even in the presence of cholesterol), the cholesterol adsorbing activity was nil. Use of DMSO as the cross-linking solvent is necessary for the imprinting, since β-CyD molecules form inclusion complexes with cholesterol in this solvent and thus their mutual conformation in the polymer is regulated appropriately for cholesterol binding. The adsorbed cholesterol was completely removed from the polymers by treating the adducts with ethanol, indicating a strong potential for practical applications.     

Molecular recognition of a self-assembled monolayer of a polydithiocarbamate derivative of β-cyclodextrin on silver

The synthesis and molecular recognition properties of a new sulfur containing β-cyclodextrin (β-CD) derivative chemisorbed on a silver surface are described. Hepta-6-amino-6-deoxy-β-CD was allowed to react with CS₂ in the presence of ammonia to give a mixture of partially substituted dithiocarbamate derivatives with an average degree of substitution of 4.5. A modified silver electrode with this derivative is capable of discriminating between the three positional isomers of nitrobenzoate ion and nitrophenol, as determined by cyclic voltammetry. Only the meta- and para-isomers give a signal corresponding to the reduction of the nitro group. This is attributed to the different orientations of the nitro group with respect to the silver surface after inclusion in the CD cavity. Experiments in the presence of cyclohexanol showed a decrease in signal intensity of the meta- and para-isomers which is associated with the competitive complexation of this guest, suggesting that the electroactive probe is complexed to the cavity.     

Aggregation behavior of amphiphilic D-p -A molecules bearing recognition group

Aggregation behavior of two amphiphilic D-π-A molecules bearing barbituric acid as both recogniton group and electron-drawing substituent , 5-(4-dodecyl oxybenzylidene)-(1H, 3H)- 2,4,6-pyrimidine trione (PB12) and 5-(4-N,N-didodecyl aminobenzylidene)-(1H,3H)-2,4,6-pyrimidine trione (AB12) was studied by UV-visible, fluorescence, and surface voltaic spectroscopies (SPS). The experimental results indicate that PB12 tends to form J-aggregate and AB12 tends to form H-aggregate under increasing concentration. An intramolecular twisted charge transfer (TICT) emission around 500 nm is observed when J-aggregate is formed between PB12 molecules, and an excimer emission around 600 nm is observed when H-aggregate is formed between AB12 molecules.     

Pattern recognition methods in the study of thermal decomposition of α-amino acids

There are many examples in the literature of a strict relation between the pathways of decomposition of a drug substance and chemical structure of its molecule. For this reason, a study has now been performed on the relation between thermal decomposition of ??-amino acids and their chemical structure. To achieve this goal, a group of a dozen or so compounds was chosen at random, and the results obtained using the DTA, TG and DTG analyses of their thermal decomposition were interpreted by highly advanced multivariate methods, principal component analysis and cluster analysis. By this statistical analysis, the influence of specific functional groups on thermal decomposition of ??-amino acids was determined. It has been found that first two principal components explain together more than 75?% of variance, and in an exceptional case, about 90?%. The third stage of decomposition was that at which the thermoanalytical data were best correlated with chemical constitution of a compound. It has also been recognized that a better discrimination among the analysed compounds was obtained for the DTA data set. The results can be useful for identification of a relation between the pathway of degradation of a drug substance and chemical structure of its molecule, and for predicting chemical stability of the compounds studied.     

NMR studies of conformations and molecular recognition of pyridinio-appended and nicotinamide-appended β-cyclodextrin

Abstract

The conformations of pyridinio-appended β-cyclodextrin (CDP⁺) and nicotinamide-appended β-cyclodextrin (CDNA⁺) were studied by NMR spectroscopy. The orientations of the pyridine residue of CDP⁺ and the nicotinamide residue of CDNA⁺ were determined by using a combination of NMR spectroscopic techniques. NMR spectra indicate that the shapes of the cavities of CDP⁺ and CDNA⁺ were changed after forming complexes. This change depended on the shape of the guest. CDNA⁺ could separate the ¹H resonances at the Cβ position of racemic tryptophan into two sets of resonances for each enantiomer.     

Simultaneous enhancement of phosphorescence and chirality by host–guest recognition of molecular tweezers

A novel type of host–guest recognition systems have been developed on the basis of a Au(III) molecular tweezer receptor and chiral Pt(II) guests. The complementary host–guest motifs display high non-covalent binding affinity (K_a: ～10⁴ L/mol) due to the participation of two-fold intermolecular π–π stacking interactions. Both phosphorescence and chirality signals of the Pt(II) guests strengthen in the resulting host–guest complexes, because of the cooperative rigidifying and shielding effects rendered by the tweezer receptor. Their intensities can be reversibly switched toward pH changes, by taking advantage of the electronic repulsion effect between the protonated form of tweezer receptor and the positive-charged guests in acidic environments. Overall, the current study demonstrates the feasibility to enhance and modulate phosphorescence and chirality signals simultaneously via molecular tweezer-based host–guest recognition.     

Aggregation behavior of amphiphilic D-π-A molecules bearing recognition group

Aggregation behavior of two amphiphilic D-π-A molecules bearing barbituric acid as both recogniton group and electron-drawing substituent , 5-(4-dodecyl oxybenzylidene)-(1H, 3H)-2,4,6-pyrimidine trione (PB12) and 5-(4-N,N-didodecyl aminobenzylidene)-(1H,3H)-2,4,6-pyrimidine trione (AB12) was studied by UV-visible, fluorescence, and surface voltaic spectroscopies (SPS). The experimental results indicate that PB12 tends to form J-aggregate and AB12 tends to form H-aggregate under increasing concentration. An intramolecular twisted charge transfer (TICT) emission around 500 nm is observed when J-aggregate is formed between PB12 molecules, and an excimer emission around 600 nm is observed when H-aggregate is formed between AB12 molecules.     

Importance of aliphatic C–H hydrogen bonding on anion recognition

We have designed and synthesised new anion receptors 1 and 2, both of their C–H groups were at the α positions to carbonyl groups and further polarised by the attached polarising substituents. This enabled us to study hydrogen bonding donor ability of C–H bonds. The polarising substituents are electron withdrawing cyano group for host 1, while charged pyridinium group for host 2. As expected from charge effects, host 2 shows roughly an order of magnitude higher binding constants against various anion guests than those of receptor 1. Since the magnitude of polarisation change should be greatest for C–H group among various hydrogen bonding groups, this indicates the importance of C–H hydrogen bonding. In contrast, the relative order of binding constants was the same for both host 1 and 2. The order of association constants was found to be (CH₃)₂POO^? > CH₃COO^? > C₆H₅COO^? > Cl^? > Br^?. DFT calculation results were in good agreement with experimental binding constants and confirmed the importance of charged group substitution. In addition, receptor 1 showed the highest association constant for dimethyl phosphinate, which is implicated in many metabolic diseases.     

Biphasic recognition chiral extraction — novel way of separating pantoprazole enantiomers

This paper presents a biphasic recognition chiral extraction system developed as a new chiral separation technology for the separation of pantoprazole enantiomers, combining a hydrophilic β-CD derivative in the aqueous phase and a hydrophobic tartaric acid in the organic phase which preferentially recognise the (R)-enantiomer and (S)-enantiomer, respectively. In this study, a number of factors which influence the efficiency of the extraction were investigated including types of organic solvents, β-CD and tartaric acid esters and their concentrations, pH and temperature. As a result, enantioselectivity for pantoprazole enantiomers can be improved up to 1.42 under optimised conditions; in addition, it is clear that the combined action of β-CD and tartaric acid esters leads to formation of the biphasic chiral extraction system with a stronger separation capacity than a monophasic chiral extraction system.     

Molecular recognition of α-amino acid esters with arylporphyrin zinc complexes

The recognition ability of 10 arylporphyrin zinc complexes with respect to glycine, -alanine, and leucine methyl esters in toluene at 20°C was studied by spectrophotometric titration. The formation of amino acid-porphyrin associates, depending on the substitution pattern in the macroring, was examined by ¹H NMR spectroscopy. The zinc complex with diarylporphyrin having hydroxy groups in the para positions of the benzene rings was found to be the best recognizing agent with respect to glycine methyl ester, while leucine methyl ester was recognized best by the complex with hydroxy groups in the ortho positions of the benzene rings.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 9, 2004, pp. 1557–1562.Original Russian Text Copyright © 2004 by G. Mamardashvili, Storonkina, N. Mamardashvili.This revised version was published online in April 2005 with a corrected cover date.     

Host-guest sensory system of sodium anthranilate-modifiedβ-cyclodextrin: Molecular recognition properties

Sodium anthranilate-modified-cyclodextrin (1) has been prepared as a sensor for detecting organic compounds including terpenoids and steroids.1 shows a pure monomer fluorescence whose intensity is increased or decreased upon addition of the guest species examined. In this system, the sodium anthranilate moiety acts either as a spacer, which enables the cyclodextrin to form a 11 guest complex by narrowing the-cyclodextrin cavity or acts as a hydrophobic cap.1 shows a higher sensitivity for terpenoids than for steroids, but has a higher selective molecular recognition ablity for steroids than for terpenoids.     

Screening of a molecularly imprinted sol–gel library for nafcillin recognition

Properties of tailored imprinted sol–gels are extremely dependent on the synthesis conditions and on the nature of the reagents used due to the diversity of combinatory interactions among the sol–gel components and the large number of chemical requirements for the sol–gel process. In this paper, methyltrimethyl orthosilicate was used as precursor to create molecularly imprinted polymers against the β-lactamic antibiotic nafcillin under different experimental conditions. A 22 member–library of imprinted sol–gels against nafcillin, and the respective control materials, was produced. Screening of the library members was performed by room temperature phosphorescence (RTP) flow-injection analysis and by batch RTP re-binding assays. A 2² factorial experimental design was also performed in selected sub-libraries of imprinted sol–gels as a function of the template and the additive concentrations, both using acid and basic catalysis.     

Molecular recognition of naphthalenediamine by polyamine modified β-cyclodextrin:yttrium metal complexes

The 6-OH group of β-cyclodextrin was modified by diethylene triamine and triethylene tetramine, respectively, mono[6-diethylenetriamino]-6-deoxy-β-cyclodextrin (DTCD) and mono[6-triethylenetetraamino]-6-deoxy-β-cyclodextrin (TTCD) were synthesized, which included 1,5-naphthalenediamine and 1,8-naphthalenediamine, respectively, in the presence of rare earth metal yttrium chloride. As a result, four ternary inclusion complexes (host–guest-metal) formed, which were characterized via ¹HNMR spectroscopy. The chemical shift variations of host and guest molecules were studied. The stoichiometric proportion of host and guest molecules is 2:1 for all the complexes. Signal degeneration still exists for the guest molecules after the inclusion process, which verifies the symmetrical conformation of guest molecules inside the cavities of two host molecules. All the four complexes exhibit “sandwich”-typed structure.     

Immune recognition of cytochrome c I. — Molecular requirements for antibody recognition and immune response stimulation studied in vitro with synthetic peptides

The epitope specificity of antibodies to horse cytochrome c (cyt.c) in the primary and secondary immune response of C57BL mice was studied by means of the ELISA technique with synthetic peptides of cyt.c. It was found that, in the early primary response, N- and C-end fragments of cyt.c (peptides 2–13, 14–22 and 92–104) were preferentially recognized. In the secondary response, more antibodies to the epitopes of the central part of the molecule (peptides 61–69 and 46–56) were found. This was presumed to be due to the mode of cyt.c processing and presentation in the course of immune response: at first, cyt.c was recognized in the native form and then in the processed one. The capacity of cyt.c peptides to stimulate the formation of cyt.c-specific antibody-secreting cells (ASC) was studied in splenocyte culture of C57BL mice. Peptides stimulated more ASC than cyt.c did, but larger molar doses of peptides were required. Comparison of the capacity of related peptides (1–13 and 2–13, 61–69, 61–77 and 57–77) to be recognized by antibodies produced to native cyt.cin vivo and to stimulate anti-cyt.c ASC in vitro suggested certain molecular requirements for cyt.c epitope and agretope formation. These were partially confirmed by computer analysis.     

Salen-based chiral fluorescence polymer sensor for enantioselective recognition of α-hydroxyl carboxylic acids

(R,R)-Salen-based chiral polymer P-1 was synthesized by the polymerization of 5,5'-((2,5-dibutoxy-1,4-phenylene)bis(ethyne-2,1-diyl))bis(2-hydroxy-3-(piperidin-1-ylmethyl) benzaldehyde (M-1) with (1R,2R)-cyclohexane-1,2-diamine (M-2) via nucleophilic addition- elimination reaction, and (R,R)-salan-based polymer P-2 could be obtained by the reduction reaction of P-1 with NaBH(4). (R,R)-Salen-based chiral polymer P-1 can exhibit greater fluorescence enhancement response toward (l)-α-hydroxyl carboxylic acids, and the value of enantiomeric fluorescence difference ratio (ef) can reach as high as 8.41 for mandelic acid and 6.55 for lactic acid. On the contrary, (R,R)-salan-based chiral polymer P-2 shows obvious fluorescence quenching response toward α-hydroxyl carboxylic acids. Most importantly, (R,R)-salen-based polymer P-1 can display bright blue fluorescence color change in the presence of (l)-α-hydroxyl carboxylic acids under a commercially available UV lamp, which can be clearly observed by the naked eyes.     

Separation of α-cyclohexylmandelic acid enantiomers using biphasic chiral recognition high-speed counter-current chromatography

This work concentrates on a chiral separation technology named biphasic recognition applied to resolution of α-cyclohexylmandelic acid enantiomers by high-speed counter-current chromatography (HSCCC). The biphasic chiral recognition HSCCC was performed by adding lipophilic (−)-2-ethylhexyl tartrate in the organic stationary phase and hydrophilic hydroxypropyl-β-cyclodextrin in the aqueous mobile phase, which preferentially recognized the (−)-enantiomer and (+)-enantiomer, respectively. The two-phase solvent system composed of n-hexane-methyl tert-butyl ether–water (9:1:10, v/v/v) with the above chiral selectors was selected according to the partition coefficient and separation factor of the target enantiomers. Important parameters involved in the chiral separation were investigated, namely the types of the chiral selectors (CS); the concentration of each chiral selector; pH of the mobile phase and the separation temperature. The mechanism involved in this biphasic recognition chiral separation by HSCCC was discussed. Langmuirian isotherm was employed to estimate the loading limits for a given value of chiral selectors. Under optimum separation conditions, 3.5–22.0 mg of α-cyclohexylmandelic acid racemate were separated using the analytical apparatus and 440 mg of racemate was separated using the preparative one. The purities of both of the fractions including (+)-enantiomer and (−)-enantiomer from the preparative CCC separation were over 99.5% determined by HPLC and enantiomeric excess reached 100% for the (±)-enantiomers. Recovery for the target compounds from the CCC fractions reached 85–88% yielding 186 mg of (+)-enantiomer and 190 mg of (−)-enantiomer. The overall experimental results show that the HSCCC separation of enantiomer based on biphasic recognition, in which only if the CSs involved will show affinity for opposite enantiomers of the analyte, is much more efficient than the traditional monophasic recognition chiral separation, since it utilizes the cooperation of both of lipophilic and hydrophilic chiral selectors.     

Molecular recognition by indoleacetic acid-imprinted polymers – effects of 2-hydroxyethyl methacrylate content

Molecularly imprinted polymers for indole-acetic acid were prepared by co-polymerizing N,N-dimethylaminoethyl methacrylate, 2-hydroxyethyl methacrylate (HEMA), and ethylene glycol dimethacrylate. The dependence of the affinity and selectivity of the imprinted polymers on HEMA content was evaluated chromatographically. The affinity was improved by increasing the HEMA content; the selectivity of the imprinted polymer was best when the HEMA content was approximately 30%, irrespective of monomer content.     

Pattern recognition applied to vapour-phase infrared spectra: characteristics of νOH bands

With the commercial availability of infrared spectrum libraries in computer accessible form, a new application of these libraries, the investigation of structure-spectrum correlations, has become possible in addition to the conventional application, the identification of unknown substances on the basis of spectral search in the library. This paper deals with the νOH bands of alcohols, also including diols and diol monoether type compounds, investigating correlations between chemical structure and the features of spectra. For monoalcohols, the frequencies measured in dilute solution and vapour phase, respectively, are correlated; the former were taken from literature, the latter from the vapour phase spectrum library of EPA. For the other types of compound, vapour phase νOH frequencies of free and hydrogen bonded hydroxy groups were studied, and the differences correlated with the hydrogen bonded structures.Peak maxima were determined by a peak picking program; in the case of overlapping bands Fourier self-deconvolution was applied prior to peak picking. For more seriously overlapping bands least-squares curve fitting was applied. In studying correlations, a cluster analysis method (KMEANS) was also used.