Benzene-based tripodal isothiouronium compounds as sulfate ion receptors

Novel benzene-based tripodal isothiouronium receptors are synthesized for the selective recognition of tetrahedral oxoanions. The binding study by isothermal titration calorimetry indicates that the cationic receptors bind sulfate ions preferably in a tripodal mode, while they show a mixed binding mode toward phosphate ion. The tripodal isothiouronium receptors show large ΔG⁰ values toward sulfate ions in methanol, which are entropy driven. The results demonstrate that a subtle structural constraint can lead to different binding modes toward structurally similar anions.     

硝基取代苯腙类荧光受体的阴离子识别与传感性能

合成了含萘荧光基团的硝基取代苯腙类受体,利用紫外-可见分光光度法、荧光发射光谱法和核磁等方法研究了受体的阴离子识别与光化学传感性能. 结果表明,在DMSO有机溶剂体系中,单硝基取代受体选择性比色和荧光识别氟离子,而双硝基取代受体可以比色和荧光识别氟离子和醋酸根离子. 归因于腙=N-NH基团质子酸性的进一步增强,双硝基取代受体能够在DMSO-H2O体系中实现对氟离子的比色和荧光识别. 此类受体是有效的“off-on”型阴离子荧光传感分子.     

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.     

酰氨基硫脲类新型分子钳受体的合成及其对氟离子的识别性能研究

本文设计并高产率合成了三种新型阴离子识别受体化合物,它们对F-的识别选择性较卤素其他阴离子的高。其对F-的识别性能通过紫外—可见光谱和核磁共振氢谱进行了检测,光谱数据表明,在DMSO溶液中受体与F-通过氢键相互作用形成1:1配合物。与以前我们报道的受体化合物相比,由于此类分子钳受体化合物具有更多的阴离子识别位点,因此具有更好地阴离子识别性能。     

间苯二甲醛缩双芳氨基硫脲的合成及阴离子识别研究

设计合成了5种间苯二甲醛缩双芳氨基硫脲受体分子, 利用紫外-可见吸收光谱及1H NMR, 考察了其与F-, Cl-, Br-, I-, CH3COO-, HSO-4, NO-3和H2PO-4等8种阴离子的作用. 当在受体分子S0, S1, S2, S3和S4的DMSO溶液中加入F-和CH3COO-四丁基铵盐的DMSO溶液时, 吸收光谱发生显著红移, 溶液颜色由无色变为深黄色, 而加入其它阴离子则无显著变化, 可以实现对这两种阴离子的裸眼检测及光谱分析. 计算结果表明, 随着苯环上取代基的变化, 此5种受体分子对F-和CH3COO-的识别作用呈现规律性变化. 1H NMR 及质子溶剂效应进一步证明了受体分子与阴离子之间以氢键作用方式相结合. Job工作曲线表明, 该类受体分子与阴离子形成1∶1的氢键配合物.     

一类缩双芳氨基硫脲受体的合成及阴离子识别

缩双芳氨基硫脲;合成;阴离子识别;氢键作用     

Initial structural studies of charged receptors that bind to inorganic phosphate anion and to an anionic phospholipid found in bacterial membranes

ITC titration studies of a family of bis-ammonium receptors based upon a scaffold of two bis-linked phenol rings show that several of the receptors bind to both dihydrogenphosphate and phosphatidylglycerol anions in a similar binding motif. Thermodynamic properties determined from ITC show that anion binding is entropy driven. Job plots determined from (1)H NMR clearly demonstrate that anion-receptor binding stoichiometry is dependent on the receptor's length of its bis-amine linkage.     

Synthetic receptors for the differentiation of phosphorylated peptides with nanomolar affinities

Artificial ditopic receptors for the differentiation of phosphorylated peptides varying in i+3 amino acid side chains were synthesized, and their binding affinities and selectivities were determined. The synthetic receptors show the highest binding affinities to phosphorylated peptides under physiological conditions (HEPES, pH 7.5, 154 mM NaCl) reported thus far for artificial systems. The tight and selective binding was achieved by high cooperativity of the two binding moieties in the receptor molecules. All receptors interact with phosphorylated serine by bis(ZnII-cyclen) complex coordination and a second binding site recognizing a carboxylate or imidazole amino acid side chain functionality.     

Tailored polymer-supported templates in dynamic combinatorial libraries: simultaneous selection, amplification and isolation of synthetic receptors

The thermodynamically controlled synthesis and isolation of macrocyclic receptors from dynamic combinatorial libraries has been achieved in a single step using a polymer-supported template. The templates were cinchona alkaloids which show interesting enantio- and diastereoselective molecular recognition events in libraries based on pseudo-dipeptide building blocks. The synthetic routes used to derivatise the alkaloids and attach them to polymer supports minimised any influence of the tethering linkage on the templating activity. Systematic studies have been carried out to probe how the polymer morphology and the template loading affect the selectivity and isolation yield of the macrocyclic receptors. Molecular recognition between solid-phase bound templates and selected receptors also enabled their affinity-type chromatographic separation.     

Dynamic combinatorial development of a neutral synthetic receptor that binds sulfate with nanomolar affinity in aqueous solution

Using dynamic combinatorial disulfide chemistry we have developed a new generation of neutral synthetic receptors for anions, based on a macrobicyclic peptide structure. These receptors show an exceptional affinity and selectivity for sulfate ions in aqueous solution [log K(a) = 8.67 in 41 mol% (67 volume%) acetonitrile in water]. The high affinity depends on a delicate balance between rigidity and flexibility in the structure of the receptor.     

A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor

GABA(C) (rho) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which includes nicotinic acetylcholine (nACh), 5-HT(3), and glycine receptors. As in other members of this family, the agonist binding site of GABA(C) receptors is rich in aromatic amino acids, but while other receptors bind agonist through a cation-pi interaction to a tryptophan, the GABA(C) binding site has tyrosine at the aligning positions. Incorporating a series of tyrosine derivatives at position 198 using unnatural amino acid mutagenesis reveals a clear correlation between the cation-pi binding ability of the side chain and EC(50) for receptor activation, thus demonstrating a cation-pi interaction between a tyrosine side chain and a neurotransmitter. Comparisons among four homologous receptors show variations in cation-pi binding energies that reflect the nature of the cationic center of the agonist.     

Selective binding of two-armed diketopiperazine receptors to side-chain-protected peptides

The binding properties of two-armed receptors based on a diketopiperazine template toward side-chain-protected peptides have been elucidated. Selective binding of these diketopiperazine receptors is not limited to side-chain-free peptides, but combinatorial on-bead assays show that also side-chain-protected peptides are recognized with high specificity. Furthermore, the screening of several dye-marked diketopiperazine receptors against an encoded side-chain-protected tripeptide library demonstrated not only their high binding specificities but also revealed that small structural changes suffice to alter the binding preferences significantly.     

三足苯甲酰基硫脲类离子受体的合成及识别性能

本文设计并合成了两种新型含酰基硫脲结构单元的三足受体1和2,并对其结构进行了表征确证。研究表明该类受体化合物对F^-、Ac^-和CN-表现出良好的紫外识别能力,由于受体1分子内电荷转移作用较强,故对阴离子表现出裸眼识别性能。紫外滴定表明,该类化合物对F^-和CN^-具有更好的结合能力;核磁滴定表明,阴离子通过分子间氢键与受体化合物结合形成主客体配合物,在高浓度F^-时受体化合物发生脱质子行为。此外,该类化合物对Hg^2+具有一定的荧光选择性识别能力。     

Exploration of the Chiral Recognition of Sugar‐Based Diindolylmethane Receptors: Anion and Receptor Structures

In this study, we have conducted a systematic investigation of the chiral recognition of carboxylic anions by D ‐glucuronic acid/diindolylmethane receptors. We investigate the influence of the anion structure on chiral recognition in the diindolylmethane/glucuronic acid‐based receptor 1 a . We found that presence of an additional hydrogen‐bond donor at the α position to the carboxylic function is essential for effective chiral differentiation in these systems. Furthermore, we present a synthetic procedure that allows for the synthesis of sugar‐decorated receptors that possess a modified substituent at the anomeric position. Four new receptors 1 b – e have been synthesized, and their chiral‐discrimination ability toward model carboxylates is studied. The obtained results show that the chiral recognition of these receptors can be fine‐tuned by incorporation of a proper substituent into the receptor structure.     

Experimental and computational studies of anion recognition by pyridine-functionalised calixarenes

Calix[4]arene-based receptors linked to amide and pyridine moieties have been synthesised in four steps from calix[4]arene, and characterised by ¹H and ¹³C NMR spectroscopy. The recognition properties of these receptors towards different anions were evaluated using ¹H NMR and computational studies. The receptors show modest selectivities towards dihydrogen phosphate versus carboxylates.     

Anion binding versus intramolecular hydrogen bonding in neutral macrocyclic amides

Although amide groups are important hydrogen-bond donors in natural and synthetic anion receptors, studies on structure-affinity relationships of amide-based macrocyclic receptors are still very limited. Therefore, we synthesized a series of macrocyclic tetraamides 5-8 derived from 1,3-benzenedicarboxylic (isophthalic) acid and aliphatic alpha,omega-diamines of different lengths. (1)H NMR titrations in DMSO solution show that the anion affinity of these receptors decreases with increasing size of the macrocycle irrespective of the anion, and this suggests a minor role of geometric complementarity. Comparison with their previously studied pyridine congeners reveals that the isophthalic acid based macrocycles are less potent, in contrast to what was found for simple model diamides. Combined theoretical and experimental structural studies were carried out to determine the reasons behind this behaviour. The results show that the unexpectedly low anion binding ability of the isophthalic acid-based receptors is due to the self-complementary nature of the isophthalic bis-amide fragments: when two such moieties are present within a sufficiently flexible macrocycle, they adopt syn-anti conformations and bind each other by two strong intramolecular hydrogen bonds that close the macrocyclic cavity. Nevertheless, anion binding is able to break these hydrogen bonds and switch a macrocycle into a convergent all-syn conformation. Despite the ill-preorganized conformation, 20-membered receptor 6 is better than either its open-chain analogue (macrocyclic effect) and/or its isomer having differently placed carbonyl groups. The crystal structures of four anion complexes of the macrocyclic receptors are reported. X-ray studies and solution NMR data confirmed the inclusive nature of the complexes and pointed to strong involvement of aromatic CH hydrogen atoms in anion binding.     

A ligand-based approach to mining the chemogenomic space of drugs

The practical implementation and validation of a ligand-based approach to mining the chemogenomic space of drugs is presented and applied to the in silico target profiling of 767 drugs against 684 targets of therapeutic relevance. The results reveal that drugs targeting aminergic G protein-coupled receptors (GPCRs) show the most promiscuous pharmacological profiles. The detection of cross-pharmacologies between aminergic GPCRs and the opioid, sigma, NMDA, and 5-HT3 receptors aggravate the potential promiscuity of those drugs, predominantly including analgesics, antidepressants, and antipsychotics.     

Design of steroid-based imidazolium receptors for fluoride ion recognition

New deoxycholic acid-based cyclic receptors bearing imidazolium and benzimidazolium moieties bridged with o-xylelene and 1,8-dimethylenenaphthalene groups have been synthesized. Anion binding studies using ¹H NMR revealed that receptors having naphthalenic group as spacer exhibit very high selectivity for fluoride ion over other anions while receptors with o-xylelene group show a preference for the chloride ion.     

Role of Toll-Like Receptor 3, RIG-I,and MDA5 in the Expression of Mesothelial IL-8 Induced by Viral RNA

Interleukin-8 (IL-8) is a chemokine that has been shown to be a potent chemoattractant for polymorphonuclear neutrophils from the vascular compartment into the pleural space during infectious pleural effusions. Mesothelial cells express the viral receptors Toll-like receptor 3 (TLR3), RIG-I, and MDA5. Activation of these receptors by viral RNA exemplified by poly (I:C) RNA leads to a time- and dose-dependent increase of mesothelial IL-8 synthesis. To show the specific effect of viral receptors, knockdown experiments with short interfering RNA specific for TLR3, RIG-I and MDA5 were performed. This novel finding of functional expression of these viral sensors on human mesothelial cells may indicate a novel link between viral infections and mesothelial inflammation and indicates a pathophysiologic role of viral receptors in these processes.     

Supramolecular Polymeric Macrocyclic Receptors – Hybrid Carrier versus Channel Transporters in Bulk Liquid Membranes

The synthesis of heteroditopic macrocyclic ureido-receptors is described. NMR studies show the formation of self-organized oligomeric superstructures. Membrane transport experiments show a direct relation between the self-assembling and the transport properties of these molecular information transfer devices. The self-organization of these receptors may provide the first evidence for the possible hybrid transport carrier versus channel mechanisms in liquid membranes.