核磁共振光谱法在固相合成中的应用及进展

目的介绍近年来NMR技术在固相合成中的应用情况及进展。方法根据常见的用于测定核磁共振信号的原子核的不同 ,对核磁共振光谱进行分类叙述。结果与结论对于固相合成 ,传统的分析方法不适合分析与树脂相连的化合物 ,严重限制了固相合成的进一步发展。随着魔角自旋技术等一系列新技术的发展和应用 ,NMR光谱法不仅可以基本满足固相合成的需要 ,还能在一定程度上促进它的发展。     

组合化学中的固相合成法

介绍了组合化学中建立有机小分子化合物库的固相合成法的基本概念、合成策略及其发展。     

Fmoc 策略固相合成磷酰化肽研究进展

蛋白质的磷酰化和去磷酰化对多种生命活动的调节起着关键的作用,磷酰化肽是研究这些生命调节过程中一类非常重要的物质。自 20 世纪 40 年代人类首次成功地合成出磷酰化肽以来,磷酰化肽的研究就引起了化学家和生物学家的广泛关注。由于Fmoc 固相合成策略在多肽的合成中被普遍应用,因此,Fmoc 固相合成策略也已经成为目前磷酰化肽最主要的合成手段。该文对近年来采用 Fmoc 固相合成策略进行磷酰化肽合成的方法（包括整体磷酰化法和磷酰化单体合成法）进行了总结,并对各种合成方法的优缺点进行了讨论。     

西曲瑞克的固相合成

目的 优化西曲瑞克的固相合成条件及纯化方法。方法 采用Fmoc固相合成法,以Rink Amide-AM Resin为固相载体,以DIC/HOBt或DIC/HOAt为缩合剂,采用制备型反相高效液相色谱法进行纯化。 结果 合成西曲瑞克粗肽,粗品纯度为94.8%。粗肽经制备型反相高效液相色谱纯化,所得精肽的纯度高达99%,总收率为62%。结论 该合成方法简单易行,产品纯度及收率都很高,适合用于西曲瑞克的工业化生产。     

肽核酸的固相合成方法

肽核酸（PNA）作为一类很有发展前景的非天然的反义核酸，其高效合成是将其广泛应用的基础。本文从PNA单体的合成和PNA寡聚体的合成两方面对近几年PNA的固相合成作了系统的介绍。     

微波辅助固相合成苄基保护的天冬氨酸六肽

目的 固相合成天冬氨酸六肽.方法 以Fmoc-Asp(OBzl)-OH为原料,苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯为缩合剂,微波辅助逐步接肽法固相合成,三氟醋酸切割产物肽,纯化得保护的天冬氨酸六肽.结果 产物结构经1HNMR,MS确证.结论 微波法可以显著缩短固相合成反应的时间,提高产率.     

固相合成胸腺五肽的制备高效液相纯化工艺研究

目的研究F-moc法固相合成胸腺五肽的纯化方法。方法采用制备高效液相色谱法对固相合成胸腺五肽进行纯化。结果与结论建立了适用于工业化生产的纯化工艺条件,纯化后精肽收率达到62.42%,纯度达到99.25%,并采用质谱法对纯化所得精肽进行了结构鉴定。     

组合化学知识问答

近年来发展起来的组合化学在新药筛选中已发挥了巨大作用。它虽没有改变药物发现的基本过程，但扩大了分子结构变化的范围并可运用自动化合成和筛选技术，大大加速了药物筛选的速度。本文就组合化学的原理和实践经验等１０个方面，以问答形式作了简要讨论     

组合化学与群集筛选

本文介绍组合化学和群集筛选的基本方法。组合化学方法能够同时产生极多种类、结构相关但有序变化的化合物库。群集筛选法能够对这种化合物库同时进行筛选，从中确定生物活性物质，再经分离、结构鉴定和构效关系分析，发现全新先导药物。     

固相合成血管紧张素Ⅱ及其反相高效液相色谱纯化与分析

目的用固相方法合成血管紧张素Ⅱ,建立其纯化和分析条件。方法以Fmoc-Phe-Wang树脂为固相载体,采取Fmoc/tBu正交保护固相合成策略,粗品的纯化采用制备型RP-HPLC。结果经过分析型RP-HPLC分析最后纯品的纯度>98%,并用电喷雾接口质谱分析证实了分子质量的正确性。结论用Fmoc固相法合成血管紧张素Ⅱ快速简便、操作方便而且回收率很高,最后通过RP-HPLC纯化,可以得到纯度很高的血管紧张素Ⅱ。     

The application of olefin metathesis to the synthesis of biologically active macrocyclic agents

Recent developments of the metathesis reaction in the area of biologically active molecules are presented. Scope and limitations of ring-closing metathesis to form medium and large rings are discussed and illustrated by the epothilone synthesis. Applications of the metathesis reaction related to medicinal chemistry, including solid phase synthesis and combinatorial chemistry are presented.     

药物合成策略的近期发展

综述正向合成分析、动态组合化学、绿色化学、不对称合成等药物合成策略的基本概念、原理及其应用,并介绍了近年来的相关进展。世纪之交出现的新观点、新方法和新技术使药物合成领域得到了前所未有的丰富和发展,尤其在药物合成策略方面最为突出。     

Analytical techniques for small molecule solid phase synthesis

Although resin-based chemistry offers many practical advantages over conventional solution phase for the synthesis of combinatorial libraries, effective monitoring of reactions conducted on the support remains a challenge. A number of techniques have been developed to enable the analysis of solid phase organic synthesis either by monitoring the resin-bound species directly or by the analysis of small quantities of material cleaved from the support. This review outlines some of the principles of the various techniques for the analysis of intermediates and products obtained from solid-phase chemistry.     

Organometallic chemistry on solid phase. An overview

Solid-phase organic synthesis (SPOS) is the most important method for the production of combinatorial libraries and with the development of high-throughput screening, libraries are widespread in pharmaceutical and agricultural chemistry. Amongst all the synthetic transformations successfully applied to solid phase, the use of organometallic reagents for the formation of a new carbon-carbon bond has been scarcely pursued. In this overview we collected the most recent examples of the use of organometallic reagents of Li, Mg, Cu, Zn, Si and B for C-C bond formation. The use of organometallic reagents in Pd-catalysed cross-coupling reactions was not reviewed. Highly basic organometallics as organo-lithium and -magnesium reagents have been more largely employed than cuprates and zincates, suggesting that several kinds of resins can withstand relatively strong reaction conditions.     

Excavation of lead compounds that inhibit mast cell degranulation by combinatorial chemistry and activity-guided

An allergic reaction ensues after antigen binds to mast cell or basophil high affinity IgE receptor, Fc epsilonRI, resulting in degranulation of various inflammatory mediators that produce various allergic symptoms. In this study, i) we isolated the active component for the inhibition of mast cell degranulation from the extract of leaves of Castanea crenata and identified it as quercetin; ii) we established the total synthesis procedure of quercetin; iii) using quercetin as positive control, we excavated some lead compounds that possess inhibitory activities for mast cell degranulation by screening the chemical libraries of 1,3-oxazolidine derivatives prepared by solid phase combinatorial chemistry. Some of 1,3-oxazolidine compounds possessing acetyl and 3',4'-dichlorophenyl group displayed strong inhibitory activities on Fc epsilonRI-mediated mast cell degranulation, suggesting that they can be used as lead compounds for the development of anti-allergic agents.     

Linkers for solid-phase synthesis of small molecules: coupling and cleavage techniques

Combinatorial chemistry has an impact on lead discovery as well as on lead optimization. The efficient synthesis of individual compounds, which has replaced the initial goal of synthesizing highly complex mixtures, can be carried out in solution or on a suitable support material. The role of a linker in solid-phase chemistry is to connect the starting material reversibly with the solid support. The main challenges in choosing an appropriate linker molecule are that the starting compounds can be easily attached to it, that it is chemically stable in the envisaged synthesis conditions and that it should be possible to cleave the final products with high efficiency.     

Application of combinatorial and parallel synthesis chemistry methodologies to antiparasitic drug discovery

The discovery and development of novel drugs has been influenced over the last several decades by new techniques in medicinal chemistry. Combinatorial and parallel synthesis chemistry techniques have opened up immense opportunities in drug discovery and development efforts. These techniques, which include solid phase organic synthesis and polymer-assisted synthesis in solution, have been routinely applied to a number of therapeutic areas. Despite the flurry of activity that characterized small molecule drug discovery efforts in the early 1990s, it was only during the mid to late 1990s that combinatorial chemistry began to make an impact on antiparasite chemotherapy. This review focuses on the development and application of combinatorial and parallel synthesis methodologies to antiparasitic drug discovery from the mid 1990s to the end of 2002. Much of this work applies to small organic molecules as inhibitors of parasite targets although some of the early applications were to the synthesis of enzyme substrates.     

Recent advances in the generation of chemical diversity libraries

In recent years, screening in combination with a diverse compound collection has become a powerful method for discovering leads for the ever-increasing number of new biologically active peptides, proteins, receptors, and enzymes discovered continually. As a result, the rapid generation and screening of compound libraries (collections) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombinant randomized peptide libraries (often referred to as biological diversity); (3) multiple peptide synthesis; and (4) non-peptidic synthetic libraries. The present review provides an overview of the recent advances in the field of peptide and non-peptidic synthetic libraries. The progress made thus far is broadly divided into two categories: (1) Amide based libraries. These libraries share the concepts of the peptide library strategies; much of the referenced work thus refers to peptides, reflecting the bias of the literature to date. (2) Non-amide based libraries. This promising technology combines solid phase synthesis with classical organic synthesis to provide large numbers of compounds with desirable bioavailability and pharmacokinetics for screening. The basic premise behind the second approach is that the high affinity ligands, when identified, will be much more likely to become useful therapeutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of diverse biological activity via combinatorial strategies is a fast developing branch of medicinal chemistry. We are at an early state in the development of combinatorial chemistry. However, this dramatic convergence of technologies represents a fundamental advance in medicinal chemistry and promises to play a major role in future drug discovery efforts. © 1994 Wiley-Less, Inc.     

Computer-assisted synthesis and reaction planning in combinatorial chemistry

In combinatorial chemistry, hundreds of thousands of reactions are run in parallel, on beads, or simultaneously in solution. A careful planning of these reactions is therefore of paramount importance in order to influence the products obtained in these experiments. We present here three software systems that should assist the chemist in solving problems metin combinatorial chemistry: WODCA can be used for the planning of the synthesis of combinatorial libraries. EROS is designed to model the course of chemical reactions to predict their products. CORA is a tool to analyze series of reactions such as those contained in reaction databases to derive knowledge that can be used in designing and simulating chemical reactions. This revised version was published online in June 2006 with corrections to the Cover Date.     

多样性合成与向前合成分析在药物发现中的应用

结合实例,综述多样性合成与向前合成分析的特点及其在药物发现中的应用。设计以简单的构件为起点,用组合化学技术合成结构复杂多样的小分子化合物,即应用多样性合成策略是解决各种化合物库中分子结构缺乏多样性和复杂性的有效方法,并将在药物发现中发挥巨大作用。