液相组合化学

综述了液相组合化学的研究进展，重点介绍了液相组合合成中的分离纯化方法和合成方法策略，基本分离纯化方法包括利用固相载体协助分离纯化法，相萃取分离纯化法和色谱法，主要合成方法策略有平行合成策略和索引合成策略。     

清除试剂在液相组合化学中的应用

综述了近年来清除试剂在液相组合化学中的应用,并介绍了一些采用清除试剂对液相化合物库进行分离和纯化的实例。对清除试剂进行了分类,各类清除试剂参与的液相反应以及被清除的非目标产物类型也作了相应的介绍。     

Solid-phase extraction for combinatorial libraries

Solid-phase extraction (SPE) has during the last three years emerged as a convenient method for the purification of compound libraries prepared by solution synthesis. The widespread use of SPE in combinatorial chemistry can be explained by straightforward SPE method development facilitated by the availability of numerous commercial SPE resins. High-speed automated SPE is readily accomplished by taking advantage of commercial laboratory robot systems. The present review summarizes and discusses advancements made in the use of different SPE resins and molecule tagging techniques for optimization of ion-exchange, reversed-phase, normal-phase and fluorous-phase SPE in combinatorial chemistry.     

Preparative high-performance liquid chromatography-mass spectrometry for the high-throughput purification of combinatorial libraries

Accurate results for the testing of combinatorial libraries necessitates high purity of the library members. Therefore, combinatorial libraries derived from a combinatorial solution or solid-phase synthesis often require the purification of compounds that do not achieve a certain purity threshold. This study describes that preparative high-performance liquid chromatography (HPLC)-mass spectrometry (MS) is the method of choice for the purification of large arrays of diverse compounds. The adoption of this technology to the workflow of a solution phase combinatorial chemistry laboratory producing more than 20,000 compounds per year is described. Furthermore, the setup and logistics are discussed as well as the purity achievable for large libraries. Efficiency, speed, quality, and universality of preparative HPLC-MS are presented in detail for a library of 140 compounds, including data logistics and downstream processes as well.     

Efficient Cleavage–Cross-Coupling Strategy for Solid-Phase Synthesis—A Modular Building System for Combinatorial Chemistry

A new modular building system for the combinatorial chemistry was developed on the basis of triazene linkers. Starting from an aniline system, further functional units and virtually any alkene or alkyne as terminator furnished lipophilic multicomponent systems in high yields and purities without the need for purification steps (see schematic representation).     

Chemical and biological integrity in natural products screening

Due to pressure from combinatorial chemistry and the streamlining of the drug discovery process through automated high-throughput screening technologies, pharmaceutically based natural products programs are under increasing scrutiny. However by taking advantages of technologies originally developed for high-throughput screening and combinatorial chemistry and applying them to processes considered as bottlenecks in classical natural products chemistry (purification, structure elucidation, sample availability) it is our opinion that natural products can still contribute to the effective discovery of novel bioactive and pharmaceutically relevant metabolites. We describe here several such strategies that if universally implemented, will demonstrate i) whether chemical diversity is truly being accessed, ii) that novel metabolites can be formatted in a manner appropriate for modern screening paradigms, and iii) that natural products can be rapidly identified not only for novelty and pharmaceutical relevance but to assess their true biological origin.     

Synthesis and biological evaluation of a beauveriolide analogue library

Synthesis of beauveriolide III (1b), which is an inhibitor of lipid droplet accumulation in macrophages, was achieved by solid-phase assembly of linear depsipeptide using a 2-chlorotrityl linker followed by solution-phase cyclization. On the basis of this strategy, a combinatorial library of beauveriolide analogues was carried out by radio frequency-encoded combinatorial chemistry. After automated purification using preparative reversed-phase HPLC, the library was tested for inhibitory activity of CE synthesis in macrophages to determine structure-activity relationships of beauveriolides. Among them, we found that diphenyl derivative 7{9,1} is 10 times more potent than 1b.     

Recent advances in liquid-phase combinatorial chemistry

In combination with high throughput screening, combinatorial organic synthesis of large numbers of pharmaceutically interesting compounds may revolutionize the drug discovery process. Although combinatorial organic synthesis on solid supports is a useful approach, several groups are focusing their research efforts on liquid-phase combinatorial synthesis by the use of soluble polymer supports to generate libraries. This macromolecular carrier, in contrast to an insoluble matrix, is soluble in most organic solvents and has a strong tendency for precipitation in particular solvents. Liquid-phase combinatorial synthesis is a unique approach since homogeneous reaction conditions can be applied, but product purification similar to the solid-phase method can be carried out by simple filtration and washing. This method combines the positive aspects of classical solution-phase chemistry and solid-phase synthesis. This review examines the recent applications (1995-1999) of soluble polymer supports in the synthesis of combinatorial libraries.     

组合化学在功能材料合成方面的应用

组合化学方法是当今材料科学和化学领域的研究热点。组合化学方法首先在新药的合成领域得到应用, 很快就以其合成周期短、合成的样品数量大、节约经费等诸多优点而拓展到功能材料的合成等其它领域。组合化学的方法有许多种, 按照反应相的不同可以分为液相中的组合合成法和固相中的组合合成法, 固相组合合成又可以根据所选用的掩模方式的不同而分为二分阴影掩模法、四分阴影掩模法、可移动百叶窗式掩模法等几种, 可以根据材料合成的实际需求加以选择。     

Ketenes in polymer-assisted synthesis

Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.     

组合化学的研究进展

综述了组合化学的起源、发展历史及原理;介绍了化合物库建立的基本方法;同时重点阐述了组合化学的研究进展及其在药物、催化剂、材料等领域中的应用情况,并对组合化学的发展做出展望。     

Dynamic combinatorial libraries: new opportunities in systems chemistry

Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.     

Integrating virtual screening and combinatorial chemistry for accelerated drug discovery

Virtual screening is increasingly being used in drug discovery programs with a growing number of successful applications. Experimental methodologies developed to speed up the drug discovery processes include high-throughput screening and combinatorial chemistry. The complementarities between computational and experimental screenings have been recognized and reviewed in the literature. Computational methods have also been used in the combinatorial chemistry field, in particular in library design. However, the integration of computational and combinatorial chemistry screenings has been attempted only recently. Combinatorial libraries (experimental or virtual) represent a notable source of chemically related compounds. Advances in combinatorial chemistry and deconvolution strategies, have enabled the rapid exploration of novel and dense regions in the chemical space. The present review is focused on the integration of virtual and experimental screening of combinatorial libraries. Applications of virtual screening to discover novel anticancer agents and our ongoing efforts towards the integration of virtual screening and combinatorial chemistry are also discussed.     

Phase-transfer dynamic combinatorial chemistry

A two-phase approach to dynamic combinatorial chemistry is described using disulfide exchange chemistry; the use of two phases significantly increases the possibilities and the scope of dynamic combinatorial chemistry by facilitating the combination of otherwise incompatible building blocks.     

Combining combinatorial chemistry and affinity chromatography: highly selective inhibitors of human betaine: homocysteine S-methyltransferase

A new method to find novel protein targets for ligands of interest is proposed. The principle of this approach is based on affinity chromatography and combinatorial chemistry. The proteins within a crude rat liver homogenate were allowed to interact with a combinatorial library of phosphinic pseudopeptides immobilized on affinity columns. Betaine: homocysteine S-methyltransferase (BHMT) was one of the proteins that was retained and subsequently eluted from these supports. The phosphinic pseudopeptides, which served as immobilized ligands for the isolation of rat BHMT, were then tested for their ability to inhibit human recombinant BHMT in solution. The most potent inhibitor also behaved as a selective ligand for the affinity purification of BHMT from a complex media. Further optimization uncovered Val-Phe-psi[PO(2-)-CH(2)]-Leu-His-NH(2) as a potent BHMT inhibitor that has an IC(50) of about 1 microM.     

Multicomponent reactions and combinatorial chemistry

Multi-component reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules for drug discovery. Due to the large number of accessible compounds, this type of chemistry has become very popular between scientists who are working in the area of combinatorial chemistry. Over the last decade combinatorial chemistry has evolved from the synthesis of great quantity of simple compounds to the parallel synthesis of complex molecules with a widely varied structure. MCRs are ideally suited for this trend, being free of limitations of a traditional multistep synthesis. The close connection and interference of multicomponent reactions and combinatorial chemistry are discussed in this review.     

Solid-phase synthesis of heterocyclic aromates: applicability towards combinatorial chemistry; a review

Because of their biological activity, stability in vivo, the rigid spatial positioning of their substituents, and their synthetic challenges, heterocyclic aromates continue to be of interest to both academic and industrial medicinal chemists. Currently, many drug-like heterocyclic aromates are prepared via solid-phase organic chemistry methods. This review examines the applicability of those methods towards combinatorial chemistry with respect to the basic demands of such an approach: 1) synthesis, work-up and subsequent purification should be easily automated enabling the efficient simultaneous synthesis of large numbers of highly pure compounds in a minimum amount of time, 2) large diversity among the ligands to be synthesized, 3) high conversion rates of the individual reaction steps, and 4) the use of commercially available starting materials. Although many methods have been developed for the synthesis of heterocyclic aromates, very few of the available methods enable the synthesis of highly diverse heteroaromatic libraries.     

聚乙二醇支载的杂环化合物库的液相合成

随着组合化学的迅速发展, 兼容固相合成和溶液相合成优点的液相合成方法已成为实现组合化学的一条重要途径. 综述了近年来聚乙二醇为可溶性聚合物载体支载的杂环化合物库的研究, 并展望了其今后的发展方向.     

组合化学法在筛选真空紫外荧光材料中的应用

综述了近年来组合化学法在筛选新型真空紫外荧光材料研究方面取得的进展, 包括组合材料库的并行合成和高通量表征技术, 并重点介绍了组合材料库的设计艺术, 最后列举了组合化学法筛选真空紫外荧光材料体系研究的实例及结果.