含氮杂环类阴离子受体*

含氮杂环类阴离子受体是目前超分子阴离子识别领域研究的热点之一。此类受体具有主体结构丰富、可调节性强、识别范围广、选择性强、灵敏度高等优点。本文综述了以吡咯、吲哚、咪唑、吡唑等含氮杂环为识别基团的阴离子受体的设计原理、识别性能和机理,展望了该领域的发展方向。     

Hormone-induced modification of EGF receptor proteolysis in the induction of EGF action.

A proposal that EGF action is mediated through enhanced internalization of EGF receptors is modified to account for more recent evidence. EGF receptors turn over at a rapid rate, and the maintenance of a steady state of EGF receptors on the cell surface is provided through a rapid synthesis of EGF receptors, balancing their removal. This rapid turnover of unoccupied receptors may arise through their internalization and proteolysis in the lysosomes, in much the same way as receptors are internalized and degraded when exposed to EGF, which enhances internalization. This provides a dilemmma for the endocytic activation concept, since slight enhancement of receptor internalization gives rise to a strong hormone response. This problem may be solved by the observation that EGF induces a change in its receptor, exposing an otherwise unavailable site for proteolytic cleavage. This hormone-dependent modification of receptors may be the critical step in the induction of responses to EGF and other hormones that are internalized with their receptors. Both platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are shown to down-regulate EGF receptors, though transiently, placing still more stringent requirements on the specificity by which hormones might act through endocytic activation of their receptors.     

Cell‐Derived Vesicles for Single‐Molecule Imaging of Membrane Proteins

A new approach is presented for the application of single‐molecule imaging to membrane receptors through the use of vesicles derived from cells expressing fluorescently labeled receptors. During the isolation of vesicles, receptors remain embedded in the membrane of the resultant vesicles, thus allowing these vesicles to serve as nanocontainers for single‐molecule measurements. Cell‐derived vesicles maintain the structural integrity of transmembrane receptors by keeping them in their physiological membrane. It was demonstrated that receptors isolated in these vesicles can be studied with solution‐based fluorescence correlation spectroscopy (FCS) and can be isolated on a solid substrate for single‐molecule studies. This technique was applied to determine the stoichiometry of α3β4 nicotinic receptors. The method provides the capability to extend single‐molecule studies to previously inaccessible classes of receptors.     

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.     

Highly effective acyclic carbohydrate receptors consisting of aminopyridine, imidazole, and indole recognition units

Neutral imidazole/aminopyridine- and indole/aminopyridine-based receptors, 1 and 2, have been established as highly effective and selective carbohydrate receptors. These receptors effectively recognise neutral carbohydrates through multiple interactions, including neutral hydrogen bonds and CH...pi interactions between the sugar CH groups and the aromatic rings of the receptors. The design of these receptors was inspired by the binding motifs observed in the crystal structures of protein-carbohydrate complexes. The formation of very strong complexes with beta-glucopyranoside 5, beta-maltoside 8, and alpha-maltoside 9 in organic media has been characterised by 1H NMR spectroscopy and confirmed by a second, independent technique, namely fluorescence spectroscopy. The syntheses, molecular-modelling studies, binding properties of the receptors 1 and 2 toward selected mono- and disaccharides as well as comparative binding studies with receptors 3 and 4 are described.     

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。     

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.     

Highly efficient recognition of native TpT by artificial ditopic hydrogen-bonding receptors possessing a conformationally well-defined linkage

Synthesis and binding affinity of rationally designed artificial ditopic nucleobase receptors are reported. The ditopic receptors were designed to recognize thymine-thymine dinucleotides by their two hydrogen-bonding moieties, which are connected to conformationally well-defined linkages such as ferrocene and biphenylene. The ditopic receptors exhibited a remarkably strong binding affinity for lipophilic TpT analogue in CDCl(3)/DMSO-d(6) (85:15, v/v). The binding affinity of the ditopic receptors for the dinucleotide was so high that even native TpT was extracted by them into CDCl(3). Detailed comparisons for the recognition abilities of the ditopic receptors were also conducted.     

Photochemically knocking out glutamate receptors in vivo

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isooxazole) receptors, a major subtype of ionotropic glutamate receptors (iGluRs), mediate the majority of the fast communication between neurons, and the activity-dependent trafficking of AMPA receptors at synapses plays a role in mammalian learning and memory. Here we describe the design, synthesis, and evaluation of a photoreactive AMPA receptor antagonist that provides a means of "knocking out" AMPA receptors present on the surface of cells. The antagonist, 6-azido-7-nitro-1,4-dihydroquinoxaline-2,3-dione (ANQX), was designed by introducing a photoreactive azido group onto a quinoxalinedione inhibitor scaffold. Computational docking of ANQX to the AMPA receptor ligand-binding core predicted efficient binding to AMPA receptors. Glutamate-evoked currents were reversibly blocked at micromolar ANQX concentrations prior to photolysis and irreversibly blocked following photolysis. ANQX provides a means of directly evaluating the trafficking of native AMPA receptors with unparalleled spatiotemporal resolution.     

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.     

双吲哚烯类受体对氨基酸的比色识别作用

设计合成了一系列3,3′-双吲哚烯类受体分子,应用紫外-可见吸收光谱研究了该类受体对二十种天然氨基酸分子的识别作用. 结果表明,在乙腈-水溶液中,双吲哚烯受体分子可以通过其氢键受体位点的质子化作用比色识别天冬氨酸、谷氨酸等酸性氨基酸;而硝基取代的双吲哚烯受体分子则通过其氢键供体位点的去质子化作用比色识别精氨酸、赖氨酸等碱性氨基酸. 在乙腈-水的中性缓冲溶液体系中,硝基取代的双吲哚烯类受体分子通过与巯基发生亲核加成反应高选择性比色识别半胱氨酸和同型半胱氨酸.     

Supramolecular analytical chemistry

A large fraction of the field of supramolecular chemistry has focused in previous decades upon the study and use of synthetic receptors as a means of mimicking natural receptors. Recently, the demand for synthetic receptors is rapidly increasing within the analytical sciences. These classes of receptors are finding uses in simple indicator chemistry, cellular imaging, and enantiomeric excess analysis, while also being involved in various truly practical assays of bodily fluids. Moreover, one of the most promising areas for the use of synthetic receptors is in the arena of differential sensing. Although many synthetic receptors have been shown to yield exquisite selectivities, in general, this class of receptor suffers from cross-reactivities. Yet, cross-reactivity is an attribute that is crucial to the success of differential sensing schemes. Therefore, both selective and nonselective synthetic receptors are finding uses in analytical applications. Hence, a field of chemistry that herein is entitled "Supramolecular Analytical Chemistry" is emerging, and is predicted to undergo increasingly rapid growth in the near future.     

A common motif in G-protein-coupled seven transmembrane helix receptors

Summary G-protein-coupled receptors all share the seven transmembrane helix motif similar to bacteriorhodopsin. This similarity was exploited to build models for these receptors. From an analysis of a multi-sequence alignment of 225 G-protein-coupled receptors belonging to the rhodopsin-like superfamily, conclusions could be drawn about functional residues. Seven residues in the transmembrane regions are conserved throughout all aligned receptors. These residues cluster at the cytosolic side of the transmembrane helices and are for all rhodopsin-like G-protein-coupled receptors implied in signal transduction. An analysis of correlated mutations reveals a number of residues, both in the helices and in the cytosolic loops, that might be important in the signal transduction pathway in subfamilies of this receptor family.     

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。     

Design and synthesis of a novel water-soluble NMDA receptor antagonist with a 1,4,7,10-tetraazacyclododecane group

Polyamines, especially spermine, inhibit N-methyl-D-aspartate (NMDA) receptors as open channel blockers. Two types of water-soluble NMDA receptor antagonist, ACCn (1) and TGCn (2), with a 1,4,7,10-tetraazacyclododecane cyclic polyamine group, were synthesized and the effects of both compounds on NMDA receptors were studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. These compounds inhibited macroscopic currents in both NR1/NR2A and NR1/NR2B receptor subtypes in oocytes voltage-clamped at -70 mV. Inhibition by the compounds of NR1/NR2A receptors were more prominent than that of NR1/NR2B receptors. The inhibitory effects of ACCn (1) on both NMDA receptors were more potent than those of TGCn (2).     

Macrocyclic anion receptors based on directed hydrogen bonding interactions

Natural anion receptors use charge-neutral dipoles to bind small anions with high affinities and selectivities. A convergent and rigid display of hydrogen bond donors such as amide, thiourea and urea functional groups in macrocyclic scaffolds would be one of the most efficient ways to create synthetic anion receptors that mimic natural ones. In this article, we present examples of natural anion receptors and discuss the synthesis of neutral macrocyclic receptors and their anion binding properties.     

新型受体呋喃并[3’,4’:5,6]吡啶并[2,3-c]吡唑的合成及对阴离子的识别研究

设计并合成了5种呋喃并[3’,4’:5,6]吡啶并[2,3-c]吡唑受体分子, 利用紫外-可见吸收光谱考察了其与F－, Cl－, Br－, AcO－, 等阴离子的作用. 结果表明该类受体分子与阴离子形成氢键配合物, 导致呋喃并吡啶并吡唑受体的光谱发生变化. 测定了配合物的结合比和稳定常数, 发现受体化合物对F－, AcO－离子具有良好的选择性, 对其它多种阴离子无影响. Job曲线表明受体分子与阴离子间形成1∶1型的配合物.     

Synthesis and Resolution of ATPO,a Potent and Selective Ampa Receptor Antagonist

Abstract

The excitatory amino acid (EAA) receptors mediate one of the major signaling systems in the central nervous system, and they are thought to be implicated in some neurodege-nerative disorders, e.g. Alzheimer's disease and stroke. It is of key importance to design selective ligands for every group of EAA receptors. The AMPA receptors are one such group of EAA receptors. (RS)-ATPO is a potent antagonist at the AMPA receptors, but it has hitherto been pharmacologically characterized only as the racemate.[1, 2]     

Synthetic mimics of mammalian cell surface receptors: prosthetic molecules that augment living cells

Specific receptors on the surface of mammalian cells actively internalize cell-impermeable ligands by receptor-mediated endocytosis. To mimic these internalizing receptors, my laboratory is studying artificial cell surface receptors that comprise N-alkyl derivatives of 3beta-cholesterylamine linked to motifs that bind cell-impermeable ligands. When added to living mammalian cells, these synthetic receptors insert into cellular plasma membranes, project ligand-binding small molecules or peptides from the cell surface, and enable living cells to internalize targeted proteins and other cell-impermeable compounds. These artificial receptors mimic their natural counterparts by rapidly cycling between plasma membranes and intracellular endosomes, associating with proposed cholesterol and sphingolipid-rich lipid raft membrane microdomains, and delivering ligands to late endosomes/lysosomes. This "synthetic receptor targeting" strategy is briefly reviewed here and contrasted with other related cellular delivery systems. Potential applications of artificial cell surface receptors as molecular probes, agents for cellular targeting, tools for drug delivery, and methods for ligand depletion are discussed. The construction of synthetic receptors as prosthetic molecules, designed to seamlessly augment the molecular machinery of living cells, represents an exciting new frontier in the fields of bioorganic chemistry and chemical biology.     

Homochiral tripodal imidazolium receptors: structural and anion-receptor studies

Two homochiral tripodal receptors were characterised by X-ray crystallography, the first examples for this class of imidazolium receptor. These receptors were also screened for anion recognition. Both receptors demonstrated selectivity towards chloride and bromide with binding constants as high as 16,000.