Molecular recognition of biotin, barbital and tolbutamide with new synthetic receptors

We have measured, by means of NMR titrations, the binding constants for the complexes between hosts N,N′-bis(6-methylpyridin-2-yl)-1,3-benzenedicarboxamide (7) and 4-chloro-N,N′-bis(6-methylpyridin-2-yl)-2,6-pyridinedicarboxamide (8, hydrated) with biotin methyl ester (1), N,N′-dimethylurea (2), 2-imidazolidone (3), N,N′-trimethylenurea (4), barbital (5) and tolbutamide (6) as guests. Molecular Mechanics calculations (Monte Carlo Conformational Search, AMBER and OPLS force fields, MacroModel v.8.1) on the complexes formed between the foregoing guests and hosts 7 and 8, comparatively with 4-oxo-N,N′-bis(6-methylpyridin-2-yl)-1,4-dihydro-2,6-pyridinedicarboxamide (9a) have been carried out in order to determine the correlation between experimental and theoretical results and to understand the behaviour of the designed new hosts. Finally we have performed single point DFT [B3LYP/6-31G(d,p)] calculations on the optimised Molecular Mechanics geometries for the complexes between hosts 7-9 and water.     

Molecular recognition of carbohydrates with acyclic pyridine-based receptors

The recognition capabilities of acyclic pyridine-based receptors toward monosaccharides were evaluated. Aminopyridine receptors based on the 2,4,6-trimethyl- or 2,4,6-triethylbenzene frame show high beta vs alpha binding selectivity in the recognition of glucopyranosides. Amidopyridine receptors, which are sterically less hindered at nitrogen, display high efficiency and an inverse selectivity. The 2-aminopyridine group has been established as a highly effective recognition group in the binding of monosaccharides. The factors influencing the binding properties of receptors 1-15, which differ in the nature and number of binding and spacer subunits used as the buildings blocks, are discussed.     

发光性受体的分子设计与分子识别

介绍了发光受体的几种典型分子识别模型。从分子识别与超分子化学的角度综述了它们在分子离子识别中的应用。对近几年发展较快的分子印迹技术及其应用进行了综述。引用文献71篇。     

Molecular recognition of carbohydrates with artificial receptors: mimicking the binding motifs found in the crystal structures of protein-carbohydrate complexes

The binding motifs found in the crystal structures of protein-carbohydrate complexes have been successfully mimicked with simple acyclic pyridine- and pyrimidine-based receptors. A full discussion of the recognition motifs observed in the crystal structures of complexes of receptors 1 and 3 with glucopyranosides 4a and 4b is provided. A remarkable similarity of these motifs to those observed in the crystal structures of sugar-binding proteins and those found by molecular modeling is shown. In addition, the recognition properties of the new pyrimidine receptor 3 toward monosaccharides 4-6 are described. This molecule has been established as a highly effective receptor for beta-glucopyranosides.     

Molecular recognition of amines and amino esters by zinc porphyrin receptors: binding mechanisms and solvent effects

Zinc porphyrin receptors bearing 12 ester groups in the meso phenyl groups (1-3) were prepared, and binding of amines and alpha-amino esters was studied with emphasis on the binding mechanisms. The X-ray crystallographic analysis of 5,10,15,20-tetrakis(2, 6-bis(carbomethoxymethoxy)-4-carbomethoxyphenyl)porphyrin (free base of 1) showed that the receptor has a binding pocket above the porphyrin plane. UV-visible titration experiments revealed that the zinc porphyrin receptors bound amines and alpha-amino esters with binding constants (K(a)) ranging from 0.5 to 52 700 M(-1) in CH(2)Cl(2) at 25 degrees C. The ester functional groups of 1 assisted the binding of aromatic alpha-amino esters (K(a) = 8 000-23 000 M(-1) in CH(2)Cl(2) at 25 degrees C) and inhibited the binding of bulky aliphatic alpha-amino esters (K(a) = 460 M(-1) for Leu-OMe in CH(2)Cl(2) at 25 degrees C), indicating that CH-pi type interactions and steric repulsions control the selectivity. The binding of amines and alpha-amino esters was tight both in a nonpolar solvent (CH(2)Cl(2)) and in a polar solvent (water) but loose in a solvent of intermediate polarity (H(2)O-MeOH (1:1)), demonstrating that two competitive driving forces are operating: (1) attractive electrostatic forces between host and guest such as coordination of the amino group to the zinc atom, and (2) entropic forces stemming from desolvation as well as enthalpic forces due to the host-guest dispersion forces. The former forces drive the binding in CH(2)Cl(2) while the latter forces drive the binding in water. The enthalpy changes in the binding in CH(2)Cl(2) and those in water range from -50 to -30 kJ mol(-1) and from -35 to 0 kJ mol(-1), respectively. The entropy changes in CH(2)Cl(2) and those in water range from -120 to -60 J K(-1) mol(-1) and from -50 to +60 J K(-1) mol(-1), respectively. Thus the binding in CH(2)Cl(2) is characterized by large negative enthalpy changes, while that in water by less negative entropy changes. These thermodynamic parameters also indicate that host-guest polar interactions (enthalpic forces) drive the binding in CH(2)Cl(2) while both host-guest dispersion interactions (an enthalpic force) and desolvation (an entropic force) drive the binding in water. Enthalpy-entropy compensation observed for the binding in water indicates that the binding of amines and amino esters in water by zinc porphyrins is associated with conformational changes as well as a high degree of dehydration. In CH(2)Cl(2), no clear compensation was observed, consistent with the mechanism that neither desolvation processes nor conformational changes contribute significantly to the binding energetics.     

Molecular recognition of insulin by a synthetic receptor

The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human insulin by the synthetic receptor cucurbit[7]uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 × 10(6) M(-1) and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and with >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7·insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus.     

Molecular recognition of carbohydrates: evaluation of the binding properties of pyrazole-based receptors and their comparison with imidazole- and indole-based systems

The aim of the study was to evaluate the potential of pyrazole-based receptors in the complexation of carbohydrates. Representatives of a new series of acyclic pyrazole-based receptors were prepared and their binding properties toward selected mono- and disaccharides evaluated. The results of the binding studies were compared with those obtained for acyclic imidazole- and indole-based receptors. The first binding studies revealed di- vs monosaccharide binding preferences of the new receptors and showed that pyrazole units are useful building blocks for the construction of receptors with interesting binding preferences.     

Enhancement of the emission intensity of fluorophore-labeled avidin by biotin and biotin derivatives. Evaluation of different fluorophores for improved sensitivity

Fluorescein, Texas Red, Cascade Blue, 7-amino-methylcoumarin-3-acetic acid, and Lucifer Yellow were evaluated as fluorescent labels for homogeneous fluorophore-linked binding assays. Conjugates of avidin with these fluorophores exhibited an enhancement in fluorescence emission in the presence of biotin or biotin derivatives. This property was used in the development of assays for biotin. The biotin-induced fluorescence enhancement of each labeled avidin were compared. Fluorescein led to the most sensitive calibration (dose-response) curve for biotin with a detection limit of 8 x 10(-10)M.     

Molecular recognition of oxoanions based on guanidinium receptors

Guanidinium is a versatile functional group with unique properties. In biological systems, hydrogen-bonding and electrostatic interactions involving the arginine side chains of proteins are critical to stabilise complexes between proteins and nucleic acids, carbohydrates or other proteins. Leading examples of artificial receptors for carboxylates, phosphates and other oxoanions, such as sulfate or nitrate are highlighted in this tutorial review, addressed to readers interested in biology, chemistry and supramolecular chemistry.     

Interaction of biotin with Mg-O bonds: bifunctional binding and recognition of biotin and related ligands by the Mg(15-crown-5)2+ unit

The interaction between biotin and the macrocyclic magnesium complex Mg(15-crown-5)(Otf)2 (15-crown-5 is 1,4,7,10,13-pentaoxacyclopentadecane, Otf(-) is trifluoromethanesulfonate anion) in solution was studied as a model for metal-biotin interactions that may be important in its speciation and function. Shifts in the solution IR spectrum establish that the interaction is dominated by ligation between the carbonyl oxygen of the ureido ring of biotin and the Mg2+ cation. However, comparative binding studies using NMR spectroscopy and conductivity reveal a substantial enthalpic contribution to binding that arises from interactions between the ureido -NH moiety and the macrocyclic ring. This is interpreted in terms of a weak-to-moderate hydrogen bond formed between the -NH group and an oxygen from the crown, which is simultaneously coordinated to Mg2+. This hypothesis is reinforced by quantitative examination of the binding of N-methylated derivatives of 2-imidazolidone, which shows that N,N'-dimethylation decreases the affinity of Mg(15-crown-5)(Otf)2 for the ligand by 2 orders of magnitude. This can be understood in terms of the structure of Mg(15-crown-5)(Otf)2. It shows a pentagonal bipyramidal coordination geometry where the five equatorial positions are occupied by the macrocyclic oxygen donors. The axial positions are occupied by weakly coordinating Otf(-) anions, which are readily displaced by biotin and related derivatives. The M-O(crown) bond distance ranges from 2.1 to 2.3 A, providing structural complementarity for the 2.2 A C=O...HN- bite distance in the ureido group, which leads to strong interaction. The contribution from hydrogen bonding illustrates the importance of second-shell interactions in the biocoordination chemistry of Mg2+. These can serve to organize cofactor interactions with biomolecules, as was recently demonstrated for a biotin-selective RNA aptamer that depends on a direct biotin-magnesium interaction for recognition of biotin (Nix, J.; Sussman, D.; Wilson, C. J. Mol. Biol. 2000, 296, 1235-1244). These results are significant in the context of the observed magnesium requirement in biotin-dependent carboxylase enzymes, where noncovalent interactions with biotin may be important in its activation toward carboxylation in the first step of biotin-dependent CO2 transfer. The synthetic system presented here also suggests that the Mg-O bond may be considered a constituent design element in the rational preparation of complexes to bind and recognize biotin.     

Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors

(-)-Cannabidiol (CBD) is a major, non psychotropic constituent of cannabis. It has been shown to cause numerous physiological effects of therapeutic importance. We have reported that CBD derivatives in both enantiomeric series are of pharmaceutical interest. Here we describe the syntheses of the major CBD metabolites, (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH) homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series. The starting materials were the respective CBD enantiomers and their DMH homologs. The binding of these compounds to the CB(1) and CB(2) cannabinoid receptors are compared. Surprisingly, contrary to the compounds in the (-) series, which do not bind to the receptors, most of the derivatives in the (+) series bind to the CB(1) receptor in the low nanomole range. Some of these compounds also bind weakly to the CB(2) receptor.     

Molecular recognition of carbohydrates by artificial receptors: systematic studies towards recognition motifs for carbohydrates

The synthesis and binding properties for carbohydrates of several artificial, acyclic receptors containing two or three heterocyclic recognition units covalently attached to a phenyl spacer is described. These host molecules having uncharged hydrogen-bonding sites were used in a systematic study towards the evaluation of recognition motifs for carbohydrates. A novel effective, acyclic hydrogen-bonding receptor possessing naphthyridine-amide moieties as heterocyclic recognition units has been developed.     

Ratiometric fluorescence sensing of phenylalanine derivatives by synthetic macrocyclic receptors

The supramolecular analytical behavior of eight pseudopeptidic fluorescent receptors (1a–c, 2a–c, 3, 4) has been studied. The receptors are either macrocyclic or open chain derivatives based on the naphthalene chromophore. The ability of 1–4 for the molecular recognition of amino acids (as Z-protected derivatives) has been evaluated in dichloromethane. The signal observed corresponds to a fluorescence emission of turn-on type. The preferential binding of all the receptors for phenylalanine (Phe) over aliphatic amino acids (Ala, Val) by a factor of 3–4 has been found. Among the family of studied fluorescent molecules, two macrocyclic receptors (1a and 1b) display high exciplex emissions and great fluorescence changes both at long (fluorescence quenching at 390 nm) and short wavelengths (fluorescence enhancement at 340 nm). This feature makes the macrocycles 1a and 1b potentially practical as fluorescent ratiometric sensors for Phe. As a proof of concept, 1a and 1b have been assayed as analytical tools for the identification of model samples enriched with Phe, mimicking the concentrations found in the pathology phenylketonuria (PKU). This result opens the door to the development of new Phe-sensing sensors based on the exciplex signaling mechanism as a new strategy for the analysis of aminoacidemias.     

Pummerer reaction of biotin sulfoxides : an access to new functionalized biotin derivatives.

Application of the Pummerer reaction to Biotin sulfoxides gives a good access to the corresponding thiolactol and thiolactone, which are key-compounds for the synthesis of new functionalized Biotin derivatives.     

Enantioselective synthetic thalidomide receptors based upon DNA binding motifs

A series of molecularly imprinted polymer (MIP) synthetic receptors selective for the sedative thalidomide (5) have been designed and synthesized based upon the functional monomer 9-(2'-methacryloyloxyethyl)adenine (2). (1)H-NMR studies were used to establish the existence of DNA-like binding interactions between 2 and the template (5). A series of ethylene glycol dimethacrylate cross-linked copolymers was synthesized using either 2 or methacrylic acid, or a combination of these functional monomers. Zonal HPLC studies demonstrated enantioselectivity (alpha = 2.11) and ligand selectivity which could be attributed to the interaction of 2 with the imide moiety of 5. Compound 2 provided a more significant contribution to the binding of 5 than methacrylic acid, though a combination of these two functional monomers resulted in improved enantioselectivity. Frontal chromatographic and batch binding studies confirmed the observed differences in affinity of the imprinted and reference polymers for the template.     

Directed molecular recognition: design and synthesis of neutral receptors for biotin to bind both its functional groups

The neutral receptors 1 and 2 are designed and synthesized for the recognition of biotin, a biologically significant molecule, in chloroform to bind completely both of its functional groups simultaneously, i.e., cyclic urea and the carboxyl groups. The truncated receptor 3 binds only the cyclic urea moiety.     

Bile acid-based cyclic bisbenzimidazolium receptors for anion recognition: highly improved receptors for fluoride and chloride ions

The anion binding properties of bile acid-based cyclic bisbenzimidazolium receptors 6-8 bridged with m-xylene, p-xylene, and 2,6-dimethylpyridine have been studied. Receptors 6 and 7 exhibit much higher binding affinity for fluoride and chloride ions, respectively, as compared to the imidazolium receptors 1 and 2. Receptor 8, however, shows high selectivity but very low binding affinity for anions due to the presence of pyridyl nitrogen. The single-crystal X-ray structure of imidazolium receptor 10-(Br)2 containing pyridyl spacer reveals the binding pattern.     

Molecular recognition of N-acetylneuraminic acid with acyclic benzimidazolium- and aminopyridine/guanidinium-based receptors

Acyclic receptors incorporating neutral and cationic recognition sites show effective binding of N-acetylneuraminic acid (Neu5Ac), the most naturally abundant sialic acid, in highly competitive solvents such as dimethyl sulfoxide (DMSO) and water/DMSO. Receptors 6b and 7b are able to form neutral/charge-reinforced hydrogen bonds and ion pairs with Neu5Ac, similar to sialic acid-binding proteins. Syntheses and binding properties of the artificial receptors are discussed.     

Protein surface recognition by synthetic receptors based on a tetraphenylporphyrin scaffold

[structure: see text] Receptors based on a tetraphenylporphyrin scaffold bearing different charged and hydrophobic groups have been synthesized. The interactions of these with horse heart cytochrome c were studied by fluorescence spectroscopy. Receptor 4 was identified to be the strongest synthetic receptor (K(d) = 20 nM) for cytochrome c. The differences in affinity among the receptors reflected a dependence on the number of anionic and hydrophobic groups.