液相法制备金属纳米粒子

液相法是在均相溶液中，利用各种途径引发化学反应，通过均相或异相成核及随后的扩散生长而制备出粒径分布窄且表面功能化的纳米尺度材料．介绍了液-液两相法、反相胶束、高温液相法等制备单分散金属纳米粒子的方法和高温液相法制备金属纳米粒子的影响因素，以及近年来在金属纳米粒子的制备和性能研究上的进展，尤其是Co等多种磁性纳米粒子的制备、磁性研究．     

Advances in organic synthesis using polymer-supported reagents and scavengers under microwave irradiation

Summary Microwave-assisted and polymer-supported organic syntheses have emerged independently as versatile tools for rapid generation of organic molecules. Chemists are increasingly looking for a combination of both techniques for efficient organic synthesis. This review covers the recent literature on organic synthesis using microwave heating in conjunction with polymer-supported reagents and scavengers.     

Carbohydrate-based combinatorial libraries

Carbohydrate-based combinatorial libraries are tremendously valuable for studying the role of sugars in biology and for expanding accessible molecular diversity needed in broad-based drug screening programs. This review discusses the issues that are relevant to the successful implementation of comprehensive carbohydrate-based combinatorial library programs. In addition, details of oligosaccharide and glycoconjugate libraries constructed using both solid phase and solution phase strategies are presented. This revised version was published online in August 2006 with corrections to the Cover Date.     

Synthetic methods for polyamine linkers and their application to combinatorial chemistry

Summary Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.     

Future pathways for combinatorial chemistry

Summary Investment in combinatorial chemistry (combichem) in the pharmaceutical industry is being driven by the need for increased efficiency. Results from pioneers in the field have demonstrated where mixture or discrete compound synthesis is useful, and what mixture sizes and compound concentrations are appropriate. To make the techniques of combichem of general utility in drug discovery, a broad range of advances is still required. Conversion of organic chemistry to solid phase conditions is key, as are developments in linkers and resins. Library design methodology requires further development. Combinatorial biosynthesis of focused libraries of natural products holds great promise for capitalising on hardwon natural product leads. Miniaturisation of screens is required to reduce the cost of screening combinatorial libraries. Developments in the processes preceding and following synthesis are required to enable the flow of increased numbers of compounds without new bottlenecks developing. The impact of combinatorial chemistry will be greatly enhanced by synergy with ongoing parallel developments in genetic technologies, screening technologies and bioinformatics.     

Discovery of enzyme inhibitors through combinatorial chemistry

Summary This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.     

Purification of combinatorial libraries

In the early days of combinatorial chemistry, much attention focused on preparation of large libraries for lead discovery. Recently, though, the focus has shifted toward smaller, more focused libraries for lead optimization. These focused libraries generally consist of individual discrete compounds. Biological assay requirements often require compounds of high purity, thus development of automated high throughput purification methods has received new attention in the past several years. This paper covers automated high throughput purification methods that have been applied to libraries of discrete compounds. Literature published through February 1998 is included. Purification methods discussed include extraction methods, scavenger methods, solid phase extraction, and preparative HPLC.     

Tools for microwave-assisted parallel syntheses and combinatorial chemistry

A protocol for transferring conventional reactions to the microwave field explores the effectiveness of parallel syntheses and combination approaches. Applicability to the reaction systems combiCHEM, multiPREP, MMR8 and HPR is defined. Model reactions have been performed in laboratory equipment. Emphasis is placed on similar reaction conditions in the individual vessels and the repeatability of results. Outcomes include esterifications and multi-center reactions exhibiting a great potential for combinatorial chemistry.     

Automating combinatorial chemistry: A primer on benchtop robotic systems

Summary Benchtop robotic systems are inexpensive, flexible automation tools with potential applications in a wide array of disciplines such as combinatorial chemistry, high-throughput screening, and genomics. We explain the basic components of a benchtop system and explore factors to consider when purchasing or customizing a robot, such as automation benefits, vendor selection, and current system limitations. Issues involving system specification, software design, and hardware customization are then discussed. Additionally, system optimization, validation, and support are detailed. Given a properly designed and implemented system, the combinatorial laboratory can markedly increase compound synthesis and purification.     

Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones

The potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving cognitive function in patients with Alzheimer's disease. Increasing the acetylcholine concentration in brain by modulating acetylcholinesterase (AChE) activity is among the most promising strategies. We have used a combinatorial approach to identify different 2,5-piperazinediones (DKP) with AChE inhibitory activity. Our goal was to find inhibitors exhibiting high AChE/BuChE (butyrylcholinesterase) selectivity, in order to reduce the undesirable side effects elicited by most of the inhibitors that have been developed to date. Screening of a DKP library constructed on solid-phase using the multiple parallel synthesis format, resulted in the identification of several compounds with moderate efficacy on AChE. In particular, DKP-80 had an IC50 = 2.2 microM with no significant inhibitory activity on BuChE. Moreover, estimated values of Clog P and log BB for the most active compounds fulfilled the bioavailability requirements for enzyme inhibitors acting on the central nervous system. In order to understand the inhibitory properties of the ligand at the molecular level, molecular dynamics simulations were computed on DKP-80 complexed to AChE, and the most relevant binding interactions of this inhibitor to the active center of the enzyme were characterized. Overall the present results indicate that the DKP-based compounds identified are novel AChE inhibitors which may be considered likely lead compounds for further development of drug candidates against Alzheimer's disease.     

硫酸氢酯类药剂浮选铜的量子化学研究

我国矿产资源日益匮乏,对浮选药剂的选择性和安全性提出了更高的要求,设计新型药剂势在必行.运用密度泛函理论,选取B3LYP/6-311+G(d, p)方法基组,对碳原子数在15～21的硫酸氢酯类浮选药剂浮选铜离子进行了计算研究.通过几何参数优化、电荷密度分布及吸附能变化,探讨了碳原子数为15～21的硫酸氢酯类浮选药剂对铜离子浮选性能的改良,综合考虑各种因素, C_(17)(十七烷基硫酸氢酯)浮选效果较好.结论对研究浮选机理及分子模拟设计新型浮选药剂具有指导意义.     

Design of new highly luminescent Tb complexes using theoretical combinatorial chemistry

The relation between the structure and luminescent properties of Tb³⁺ complexes containing β-diketonate ligands has been investigated by means of theoretical combinatorial chemistry. The new hybrid method developed combines an empirical relation involving the energy of the lowest triplet state of Tb³⁺ complexes with extremely fast semiempirical quantum mechanical calculations. The concomitant use of phenyl groups attached at both extremities of the β-diketonate ligand has shown to give rise to complexes exhibiting theoretical emission quantum yields higher than 0.5. The results indicate that the proposed method may be used as a valuable tool for predicting luminescent properties of a large number of Tb³⁺ complexes in a relatively short computational time, therefore contributing to further developments in the field of theoretical combinatorial chemistry.     

New high-throughput material-exploration system based on combinatorial chemistry and electrostatic atomization

As a tool to facilitate future material explorations, our group has developed a new combinatorial system for the high-throughput preparation of compounds made up of more than three components. The system works in two steps: the atomization of a liquid by a high electric field followed by deposition to a grounded substrate. The combinatorial system based on this method has plural syringe pumps. The each starting materials are fed through the syringe pumps into a manifold, thoroughly mixed as they pass through the manifold, and atomized from the tip of a stainless steel nozzle onto a grounded substrate.     

Discovering Echinococcus granulosus thioredoxin glutathione reductase inhibitors through site-specific dynamic combinatorial chemistry

In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine (2af) was identified, upon library analysis by HPLC (IC $_{50}$  = 24  $\upmu $ M). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure–activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine (2aj) as the best enzyme inhibitor in these series, with an IC $_{50}$  = 14  $\upmu $ M. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases.     

Discovery of a herbicidal lead using polymer-bound activated esters in generating a combinatorial library of amides and esters

Summary A combinatorial library containing mixtures of amides and esters was prepared through solid-phase chemistry. The advantages of using solid-phase chemistry over solution-phase chemistry to prepare this library are discussed. The library was screened through a high-throughput whole organism herbicidal assay upon which a mixture containing amides was found to have herbicidal activity. Deconvolution of the mixture providedN-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl)-1H-pyrazole-5-carboxamide as a herbicidal lead with broadleaf and narrowleaf pre-emergence herbicidal activity as low as 100 g/ha on some weed species. This study represents the first report of an agrochemical discovered using a combinatorial approach. Supplementary Material, comprising experimental procedures for the preparation of resin II and the reaction of II with nucleophiles, GC/MS and LC/MS data for the reaction ofII with morpholine, and a detailed experimental for the preparation of 2 with characterization data, is available upon request.     

Use of combinatorial chemistry to develop photocurable thermoplastic polyurethane elastomers (TPUs)

Combinatorial chemistry was used to develop photocurable thermoplastic polyurethane elastomers through the incorporation of photoreactive diacetylene diols as chain extenders. The methodology applied allowed, in 36 experiments, the choice of the best compromise between mechanical properties and lack of colour. The combinations chosen were scaled up and their properties were evaluated in terms of mechanical properties. The combinatorial approach reduced the estimated time tenfold in developing such type of materials.     

Solid phase synthesis of functionalized biaryl ethers: Versatile scaffolds for combinatorial chemistry

4-Fluoro-3-nitrobenzoic acid attached to a solid support was shown to react under mild conditions with a wide range of functionalized phenols to yield, after cleavage, the corresponding biaryl ethers in excellent purity. In a similar fashion, biaryl thioethers could be obtained. Further elaboration of immobilized biaryl ethers demonstrates the potential for combinatorial library generation. This revised version was published online in August 2006 with corrections to the Cover Date.     

Structure and properties of TentaGel resin beads: Implications for combinatorial library chemistry

Summary In view of the widespread use of TentaGel resin beads for the synthesis of combinatorial libraries, the properties of TentaGel resin have been examined using a combination of confocal laser microscopy and NMR spectroscopy. Evidence is presented that trypsin, a 23.5-kDa enzyme, can penetrate to the core of 90-m TentaGel beads, and that the matrix of such beads permits molecular motion at a similar rate to that in solution. The beads act as a separate gel phase rather than as a porous solid. These conclusions have important implications for the bioassay of on-bead combinatorial chemical libraries.     

Editorial: Past,present and future of the combinatorial chemistry in Spain

Molecular Diversity -     

Application of computer assisted combinatorial chemistry in antivirial,antimalarial and anticancer agents design

Combinatorial chemistry and technologies have been developed to a stage where synthetic schemes are available for generation of a large variety of organic molecules. The innovative concept of combinatorial design assumes that screening of a large and diverse library of compounds will increase the probability of finding an active analogue among the compounds tested. Since the rate at which libraries are screened for activity currently constitutes a limitation to the use of combinatorial technologies, it is important to be selective about the number of compounds to be synthesized. Early experience with combinatorial chemistry indicated that chemical diversity alone did not result in a significant increase in the number of generated lead compounds. Emphasis has therefore been increasingly put on the use of computer assisted combinatorial chemical techniques. Computational methods are valuable in the design of virtual libraries of molecular models. Selection strategies based on computed physicochemical properties of the models or of a target compound are introduced to reduce the time and costs of library synthesis and screening. In addition, computational structure-based library focusing methods can be used to perform in silico screening of the activity of Compounds against a target receptor by docking the ligands into the receptor model. Three case studies are discussed dealing with the design of targeted combinatorial libraries of inhibitors of HIV-1 protease, P. falciparum plasmepsin and human urokinase as potential antivirial, antimalarial and anti-cancer drugs. These illustrate library focusing strategies.