Neuronal activation by GPI-linked neuroligin-1 displayed in synthetic lipid bilayer membranes

We have characterized, in vitro, interactions between hippocampal neuronal cells and silica microbeads coated with synthetic, fluid, lipid bilayer membranes containing the glycosylphosphatidyl inositol (GPI)-linked extracellular domain of the postsynaptic membrane protein neuroligin-1. These bilayer-neuroligin-1 beads activated neuronal cells to form presynaptic nerve terminals at the point of contact in a manner similar to that observed for live PC12 cells, ectopically expressing the full length neuroligin-1. The synthetic membranes exhibited biological activity at neuroligin-1 densities of approximately 1 to 6 proteins/microm(2). Polyolycarbonate beads with neuroligin-1 covalently attached to the surface failed to activate neurons despite the fact that neuroligin-1 binding activity is preserved. This implies that a lipid membrane environment is likely to be essential for neuroligin-1 activity. This technique allows the study of isolated proteins in an environment that has physical properties resembling those of a cell surface; proteins can diffuse freely within the membrane, retain their in vivo orientations, and are in a nondenatured state. In addition, the synthetic membrane environment affords control over both lipid and protein composition. This technology is easily implemented and can be applied to a wide variety of cellular studies.     

Stereoselective synthesis of individual isomers of Leu-enkephalin analogues containing substituted beta-turn bicyclic dipeptide mimetics

Novel constrained beta-turn dipeptide mimetics, 8-phenyl thiaindolizidinone amino acids 3, have been synthesized stereoselectively and incorporated into Leu-enkephalin peptides as a replacement of dipeptide Gly3-Phe4 to afford four individual isomers of Leu-enkephalin analogues 6.     

Ligand-modulated stereo- and regioselective tandem addition reactions of rhenium-bound naphthalene

A series of complexes of the form TpRe(CO)(L)(eta(2)-naphthalene) (Tp = hydridotris(pyrazolyl)borate) undergoes tandem electrophile/nucleophile addition reactions with a high degree of regiocontrol depending on the auxiliary ligand, L. When L = PMe(3), the reaction of the eta(2)-naphthalene complex with triflic acid followed by a silyl ketene acetal favors the 1,4-addition product, whereas when L = pyridine, N,N-dimethylaminopyridine, N-methylimidazole, or NH(3) the 1,2-addition product is favored. These reactions proceed with excellent stereocontrol: both electrophile (H(+), D(+)) and nucleophile (silyl ketene acetal) add anti to the face of metal coordination, and a single coordination diastereomer can be isolated for each reaction. One-electron oxidation of the Re complex affords the corresponding free dihydronaphthalene in good yield.     

Photoelectron spectra of cyclic aromatic ethers : The question of the mills-nixon effect

UV photoelectron spectra (UPS) of the cyclic aromatic ethers (1; R = H, n = 1, 2) are compared with each other and with those of non-cyclic ethers. The spectrum of the chroman (1; R = H, n = 2) is clearly distinguishable from those of all the other ethers. The differences in the spectra have been interpreted in terms of differing conjugative effects of oxygen and of “hyperconjugative” effects of methylene with the aromatic ring. These conclusions are supported by MO calculations. The bearing of these differing conjugative effects on reactivity of cyclic aromatic ethers is discussed and the conclusion reached that the orientational preferences customarily explained by the “Mills-Nixon effect” do not depend upon variation of bond lengths or bond angles in the aromatic ring but upon cross-conjugation effects in “Wheland” transition states.     

Unusually sharp dependence of water exchange rate versus lanthanide ionic radii for a series of tetraamide complexes

The tetraamide ligand, DOTA-tetra(glycine ethyl ester), forms complexes with the lanthanide(III) cations that exist in solution predominantly as the square antiprism structure with single, slowly exchanging inner-sphere water molecule. Variable-temperature 1H and 17O NMR studies revealed that the bound water lifetimes in these complexes were sharply dependent upon the ionic radius of Ln3+ cation. A novel lanthanide-induced shift technique was used to unmask the bound water 17O resonance of SmL3+ and YL3+ complexes from the bulk water resonance. The bound water lifetime (tauM298) was approximately 800 mus in the EuL3+ complex but became much shorter (several microseconds) for Ln3+ cations with larger and smaller ionic radii. This demonstrates that water exchange is exquisitely fine-tuned in this macrocyclic tetraamide system and that a variety of Ln3+ complexes meet with the exchange requirement, Deltaomega*tauM >/= 1, necessary for an efficient MT agent.     

Rhenium-catalyzed coupling of propargyl alcohols and allyl silanes

A mild method for the regioselective coupling of propargyl alcohols and allylsilanes is described. The method employs an air- and moisture-tolerant rhenium-oxo complex ((dppm)ReOCl3) as a catalyst for the formation of sp3-carbon-sp3-carbon bonds without the need for prior activation of the propargyl alcohol as a halide or pseudohalide. The stability of the high oxidation state rhenium complex allows for simple reisolation and reuse of the catalyst. A broad range of functional groups is tolerated including aryl halides, olefins, esters, and acid-labile functional groups such as acetals. Furthermore, displacement of the alcohol occurs preferentially even in the presence of other electrophiles such as primary alkyl halides and conjugated esters. The use of enantiopure crotylsilanes as coupling partners allows for the asymmetric construction of two adjacent stereocenters. The potential of this reaction is demonstrated in an asymmetric synthesis of delta-lactone, di-O-methylcalopin.     

Comment: 2004's fastest organic and biomolecular chemistry!

In January 2003, the Royal Society of Chemistry launched Organic & Biomolecular Chemistry (OBC)--a journal promising to provide high quality research from all aspects of synthetic, physical and biomolecular organic chemistry. The journal was set to build upon the foundations laid down by its predecessor publications (J. Chem. Soc., Perkin Trans. 1 and J. Chem. Soc., Perkin Trans. 2) as well as complement the subject coverage already published in prestigious general chemistry journals such as Chemical Communications and Chemical Society Reviews. Nearly two years on, just how is the programme developing and what can the community expect to see from the Royal Society of Chemistry (RSC)?     

Three-dimensional hydrogen-bond geometry and probability information from a crystal survey

Summary An extensive crystal survey of the Cambridge Structural Database has been carried out to provide hydrogen-bond data for use in drug-design strategies. Previous crystal surveys have generated 1D frequency distributions of hydrogen-bond distances and angles, which are not sufficient to model the hydrogen bond as a ligand-receptor interaction. For each hydrogen-bonding group of interest to the drug designer, geometric hydrogen-bond criteria have been derived. The 3D distribution of complementary atoms about each hydrogen-bonding group has been ascertained by dividing the space about each group into bins of equal volume and counting the number of observed hydrogen-bonding contacts in each bin. Finally, the propensity of each group to form a hydrogen bond has been calculated. Together, these data can be used to predict the potential site points with which a ligand could interact and there-fore could be used in molecular-similarity studies, pharmacophore query searching of databases, or de novo design algorithms.     

Asymmetric dimers can be formed by dewetting half-shells of gold deposited on the surfaces of spherical oxide colloids

Asymmetric dimers consisting of gold microcrystals and spherical silica colloids have been fabricated by depositing thin films of gold onto the spherical colloids to form half-shells, followed by annealing at elevated temperatures. The capability and feasibility of this procedure have been demonstrated with silica and titania beads of 0.2-2 mum in diameter and gamma-Fe2O3/polystyrene@SiO2 core-shell particles 0.5 mum in size. The dimensions of gold microcrystals could be conveniently varied in the range of 100-650 nm by controlling the thickness of gold films and/or the diameter of the spherical colloids. This method provides another route to asymmetric dimers made of colloidal particles that could be different in size, chemical composition, surface functionality, density or sign of surface charge, bulk property, or a combination of these properties.     

不依赖于统计模型的手性毛细管电泳分离多指标同时优化

考虑到手性毛细管电泳分离机理的复杂性，提出了不依赖于统计模型的二进制编码遗传算法多目标优化策略。根据实验参数的多少及其重要性，采用均匀设计安排完成初步实验。并用Derringer功效函数作为多指标同时优化的评价指标，以取得较高的分离度和较快分离速度；通过对实验参数给予编码，转化为二进制字符串，根据得到的总功效函数值大小进行遗传算法操作，产生新的一组实验条件。重复上述过程直到得到最佳分离条件为止。此方法成功地应用于华法令对映体的毛细管电泳分离条件优化。