"Single sample concept": theoretical model for a combinatorial approach to solid-state inorganic materials

A theoretical model for a "single sample concept" (SSC) applied to the combinatorial chemistry of solid-state inorganic compounds is presented. The SSC is performed by reacting N starting materials (randomly mixed) in a single sample of approximately 1 cm(3). Combinatorial calculations demonstrate that the number of reasonably estimated phases to be found in the space of N components grouped into compounds (e.g. oxides, sulfides, or halogenides) containing up to q < or = 6 metallic elements is smaller than combinations set up by starting conditions for local reactions within the bulk of a single ceramic sample. Recently, the SSC proved to work in the case of synthesizing libraries of 3d metal oxides, from which magnetic particulate matter was extracted by a magnetic separation technique. The SSC may be applied in a first screening cycle followed by 2D approaches of combinatorial chemistry.     

A new [4]carceplex, and a crystal structure and dynamic combinatorial chemistry of a [5]carceplex

A new [4]carceplex (2·guest) is reported. It is composed of two cavitands linked by four disulfide bonds. It forms twistomers, which interconvert on a millisecond timescale. The energy barrier for interconversion of twistomers is guest-dependent. Formation of [4]carceplex 2·guest is template dependent. The selectivity in templates is flat relative to most previous related template work. Larger kin [5]carceplex 1·guests were reinvestigated. A crystal structure confirms the twist between the hemispherical cavitands. Use of a redox buffer allowed dynamic combinatorial chemistry to be performed between pairs of templates.     

Identification of ligands for the Tau exon 10 splicing regulatory element RNA by using dynamic combinatorial chemistry

We describe the use of dynamic combinatorial chemistry (DCC) to identify ligands for the stem-loop structure located at the exon 10-5'-intron junction of Tau pre-mRNA, which is involved in the onset of several tauopathies including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). A series of ligands that combine the small aminoglycoside neamine and heteroaromatic moieties (azaquinolone and two acridines) have been identified by using DCC. These compounds effectively bind the stem-loop RNA target (the concentration required for 50% RNA response (EC(50)): 2-58 μM), as determined by fluorescence titration experiments. Importantly, most of them are able to stabilize both the wild-type and the +3 and +14 mutated sequences associated with the development of FTDP-17 without producing a significant change in the overall structure of the RNA (as analyzed by circular dichroism (CD) spectroscopy), which is a key factor for recognition by the splicing regulatory machinery. A good correlation has been found between the affinity of the ligands for the target and their ability to stabilize the RNA secondary structure.     

基于点击化学的色谱分离材料研究新进展

自诺贝尔奖获得者Sharpless教授2001年首次提出点击化学概念以来,该类反应凭借条件温和、反应迅速、产量高、副产物少、分离提纯简单等优势,迅速拓展至材料和生命等诸多科学领域,成为一种强大的模块化合成工具。目前,点击化学反应已成为设计制备分离材料的重要手段,展现出蓬勃发展的现状。本文首先简要地回顾了点击化学的发展历程并介绍了其独特优势,然后聚焦于柱色谱和膜色谱两大分离领域,系统地综述了近5年发表的基于点击化学的色谱分离材料相关报道,重点归纳了叠氮-炔、巯基-烯和巯基-炔这3种常见点击反应类型在色谱分离材料研究中的最新进展,最后对点击化学在开发高效分离材料方面的发展前景进行了展望。     

Predicting sequences and structures of MHC-binding peptides: a computational combinatorial approach

Peptides bound to MHC molecules on the surface of cells convey critical information about the cellular milieu to immune system T cells. Predicting which peptides can bind an MHC molecule, and understanding their modes of binding, are important in order to design better diagnostic and therapeutic agents for infectious and autoimmune diseases. Due to the difficulty of obtaining sufficient experimental binding data for each human MHC molecule, computational modeling of MHC peptide-binding properties is necessary. This paper describes a computational combinatorial design approach to the prediction of peptides that bind an MHC molecule of known X-ray crystallographic or NMR-determined structure. The procedure uses chemical fragments as models for amino acid residues and produces a set of sequences for peptides predicted to bind in the MHC peptide-binding groove. The probabilities for specific amino acids occurring at each position of the peptide are calculated based on these sequences, and these probabilities show a good agreement with amino acid distributions derived from a MHC-binding peptide database. The method also enables prediction of the three-dimensional structure of MHC-peptide complexes. Docking, linking, and optimization procedures were performed with the XPLOR program [1].     

Mixed-metal (platinum, palladium), mixed-pyrimidine (uracil, cytosine) self-assembling metallacalix[n]arenes: dynamic combinatorial chemistry with nucleobases and metal species

Reactions between the mononuclear mixed-nucleobase complex [Pt(en)(UH-N1)(CH2-N3)]+ (1; en: ethylenediamine; UH-N1: uracil monoanion bonded through the N1 atom; CH2-N3: neutral cytosine bonded through the N3 atom) and [Pd(II)(en)] or [Pd(II)(2,2'-bpy)] (2,2'-bpy: 2,2'-bipyridine) lead to libraries of compounds of different stoichiometries and different connectivities. In these compounds, the palladium entity binds to or cross-links either the N3 sites of uracil and/or the N1 sites of cytosine, following deprotonation of these positions to give uracil dianions (U) and cytosine monoanions (CH). Cyclic species, which can be considered as metallacalix[n]arenes, have been detected in several cases, with n being 4 and 8. The complexity of the compounds formed not only results from the possibility of the two different nucleobases in building block 1 engaging in different connectivities with the Pd entities, but also from the potential for the formation of oligomers of different sizes and different conformations; in the case of cyclic tetranuclear Pt(2)Pd(2) species, this can, in principle, lead to the various arrangements (cone, partial cone, 1,2-alternate, 1,3-alternate) known from calix[4]arene chemistry. A further complication arises from the fact that, depending on the mutual orientation of the exocyclic groups of the two nucleobases (O2 and O4 of uracil, O2 and N4 of cytosine), these sites can be engaged in additional chelation of [Pd(II)(en)] and [Pd(II)(2,2'-bpy)]. Thus, penta-, hexa-, and octanuclear complexes, Pt(2)Pd(3), Pt(2)Pd(4), and Pt(2)Pd(6), derived from cyclic Pt(2)Pd(2) tetramers have been isolated and characterized.     

A combinatorial approach to the discovery of biocidal six-residue cyclic D,L-alpha-peptides against the bacteria methicillin-resistant Staphylococcus aureus (MRSA) and E. coli and the biofouling algae Ulva linza and Navicula perminuta

A combinatorial approach has been used to rapidly identify cyclic d,l-alpha-peptide hexamer sequences that exert biocidal activity towards both methicillin-resistant Staphylococcus aureus (MRSA) and E. coli bacteria, as well as the marine algae Ulva linza and Navicula perminuta. Evaluation of the effects against marine algae was facilitated by the development of a reliable, automated assay for toxicity, which should be of general utility for biofouling investigations. While the selective toxicity of cyclic D,L-alpha-peptides towards bacteria has been proven to be highly sensitive to minor changes in amino acid composition, this study demonstrates that this phenomenon extends to eukaryotic species as well, despite their significant structural differences. In performing toxicity assays on both prokaryotic and eukaryotic organisms in parallel, we have discovered examples of six-residue cyclic D,L-alpha-peptide sequences with either broad-spectrum or highly selective biocidal activities. Sequence [KWFFFH] (underlined amino acid abbreviations represent D-amino acid residues) was found to display 100-fold selectivity towards U. linza, demonstrating that the approach described herein may help lead to the development of new biofouling tools which are not generally toxic to all organisms, but rather specifically target microbial agents of interest.     

A new versatile linker for the solid-phase synthesis of secondary amines

A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed. The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel synthesis of a small set of different secondary amines.     

Cellular separations: a review of new challenges in analytical chemistry

The ability to generate a sample of cells of a given phenotype is a prerequisite for many cellular assays. In response to this growing need, numerous methods for cell separation have been developed in recent years. This Review covers recent progress in the field of cell separations and cell chromatography. Cell separation principles—such as size and affinity capture—are discussed, as well as conventional methods such as fluorescence-activated cell sorting and magnetic sorting. Planar flow cell arrays, dielectrophoresis, field-flow methods, and column separation devices are reviewed, as well as applications of these methods to medicine and biotechnology. Cell attachment and adhesion strategies and a comparison of techniques are also presented.     

Dynamic combinatorial carbohydrate libraries: probing the binding site of the concanavalin A lectin

Dynamic combinatorial chemistry (DCC) has emerged as an efficient approach to receptor/ligand identification based on the generation of combinatorial libraries by reversible interconversion of the library constituents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined with the plant lectin Concanavalin A as a target species. Dynamic carbohydrate libraries were generated from a pool of carbohydrate aldehydes and hydrazide linker/scaffold components through reversible acylhydrazone exchange, resulting in libraries containing up to 474 constituents. Dynamic deconvolution allowed the efficient identification of the structural features required for binding to Concanavalin A and the selection of a strong binder, a tritopic mannoside, showing an IC(50)-value of 22 microM.     

Exploring privileged structures: the combinatorial synthesis of cyclic peptides

Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. They may therefore be considered to be privileged structures. This review outlines the strategies by which both macrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines have been synthesised in combinatorial libraries. It also briefly outlines some of the biological applications of these molecules, thereby justifying their inclusion as privileged structures.     

A practical entry to C18-constrained-E-ring analogues of methyllycaconitine (MLA): a concise new stereoselective approach to 8-oxa-decahydroisoquinolines accompanied by a simple microwaves-assisted synthesis of the succinimidobenzoate appendage of MLA

A Mannich-type intramolecular cyclization afforded access to a 8-oxa-decahydroisoquinoline heterocyclic system. Good stereoselectivity was observed. A promising microwave-assisted synthesis of the methylsuccinimidobenzoate moiety of methyllycaconitine has also been carried out.     

Directed synthesis of a heterobimetallic complex based on a novel unsymmetric double-Schiff-base ligand: preparation, characterization, reactivity and structures of hetero- and homobimetallic nickel(II) and zinc(II) complexes

A series of bimetallic zinc(II) and nickel(II) complexes based on the novel dinucleating unsymmetric double-Schiff-base ligand benzoic acid [1-(3-{[2-(bispyridin-2-ylmethylamino)ethylimino]methyl}-2-hydroxy-5-methylphenyl)methylidene]hydrazide (H(2)bpampbh) has been synthesized and structurally characterized. The metal centers reside in two entirely different binding pockets provided by the ligand H(2)bpampbh, a planar tridentate [ONO] and a pentadentate [ON(4)] compartment. The utilized ligand H(2)bpampbh has been synthesized by condensation of the single-Schiff-base proligand Hbpahmb with benzoic acid hydrazide. The reaction of H(2)bpampbh with two equivalents of either zinc(II) or nickel(II) acetate yields the homobimetallic complexes [Zn(2)(bpampbh)(mu,eta(1)-OAc)(eta(1)-OAc)] (ZnZn) and [Ni(2)(bpampbh)(mu-H(2)O)(eta(1)-OAc)(H(2)O)](OAc) (NiNi), respectively. Simultaneous presence of one equivalent zinc(II) and one equivalent nickel(II) acetate results in the directed formation of the heterobimetallic complex [NiZn(bpampbh)(mu,eta(1)-OAc)(eta(1)-OAc)] (NiZn) with a selective binding of the nickel ions in the pentadentate ligand compartment. In addition, two homobimetallic azide-bridged complexes [Ni(2)(bpampbh)(mu,eta(1)-N(3))]ClO(4) (NiNi(N(3))) and [Ni(2)(bpampbh)(mu,eta(1)-N(3))(MeOH)(2)](ClO(4))(0.5)(N(3))(0.5) (NiNi(N(3))(MeOH)(2)) were synthesized. In all complexes, the metal ions residing in the pentadentate compartment adopt a distorted octahedral coordination geometry, whereas the metal centers placed in the tridentate compartment vary in coordination number and geometry from square-planar (NiNi(N(3))) and square-pyramidal (ZnZn and NiZn), to octahedral (NiNi and NiNi(N(3))(MeOH)(2)). In the case of complex NiNi(N(3)) this leads to a mixed-spin homodinuclear nickel(II) complex. All compounds have been characterized by means of mass spectrometry as well as IR and UV/Vis spectroscopies. Magnetic susceptibility measurements show significant zero-field splitting for the nickel-containing complexes (D=2.9 for NiZn, 2.2 for NiNi(N(3)), and 0.8 cm(-1) for NiNi) and additionally a weak antiferromagnetic coupling (J=-1.4 cm(-1)) in case of NiNi. Electrochemical measurements and photometric titrations reveal a strong Lewis acidity of the metal center placed in the tridentate binding compartment towards external donor molecules. A significant superoxide dismutase reactivity against superoxide radicals was found for complex NiNi.