组合化学及其在新农药创制中的应用

结合医药领域的成功经验概述了组合化学的基本概念、化合物库的合成技术与分析、筛选方法,展望了组合化学在新农药创制中的应用前景。     

组合化学与新医药新农药创制

对组合化学方法及其在新医药和新农药创制中的应用进行了简要的叙述。并介绍了在新农药创制中应用组合化学方法的成功实例。     

高通量合成与筛选在新农药创制中的应用

高通量筛选与组合合成技术相结合是发现创新药物的重要技术手段之一。这极大地提高了化合物库的建立速度及对目标分子、活性物质以及先导药物的筛选速度,在农药创制过程中可以缩短新农药分子的研发周期,提高成功率。     

新农药创新方法与应用(1)—中间体衍生化方法

介绍了一种发现新农药的创新研究方法——中间体衍生化方法。新农药创新涉及多领域间的合作,其过程非常复杂,中间体衍生化方法是从化学的角度出发,把复杂问题简单化,应用效果很好。通过多年的实践,总结其内涵有三:利用中间体进行化学反应,设计合成新化合物,然后筛选,发现先导化合物,再经优化发现新农药品种;利用简单的原料,通过化学反应合成新的中间体,利用该中间体替换已知农药或医药品种化学结构中的一部分,得到新的化合物,经进一步研究,得到新农药品种;利用已知的具有活性的化合物或农药品种作为中间体,进行化学反应,设计合成新化合物,经筛选、优化研究发现新农药品种。     

化学信息学技术在农药研发中的作用

随着计算机科学和技术,网络技术的发展,计算机在科研、生产和服务等领域都得到深入广泛的应用.化学信息学是利用信息学方法和技术解决化学问题的学科,它是计算机科学与化学交叉组合后形成的交叉学科.当今的日常生活物质已经证实化学无处不在,因此,化学信息学的方法和技术可用于与化学实体相关的所有领域:药物设计、农药设计、中药现代化、环境保护、公共安全和材料设计等.所谓化学问题主要包括:分子设计、合成设计和结构确定.而在农药研发过程中,这三项工作是研发人员的主要工作,并占据大量工作时间和研发经费.众所周知,化学信息学方法和技术已成功应用于药物设计领域.尽管农药与医药的作用对象不同,接触的人群也不同,但它们的实质都是新化学实体的研发.因此,化学信息学方法和技术同样可以在农药研发中起着提高研发效率、降低成本和污染的作用.在此,我们将介绍在国家"973"项目、国家基金委和上海科委项目资助下建立的"绿色农药设计的化学信息学技术平台".该平台包括农用化学品数据库、化合物各种性质预测、化合物结构与活性关系研究和合成设计等软件系统.     

新农药创制中除草活性评价程序及方法概述

生物活性评价是新农药创制中的重要环节,是发现与评价活性化合物的唯一依据,也对化合物结构的优化改进具有指导作用。概述了目前新农药创制中除草活性的筛选程序及一些主要评价方法。     

农药设计中的活性子叠加法

活性子（Activon）是指农药分子中具有生理活性所必需的分子片段，该片段中分布着与受体通过电荷控制和轨道控制进行键合的若干部位。通过合成手段将活性子连接起来，是发现新农药的有效方法之一。     

氮杂环卡宾有机催化合成农药活性手性分子

手性农药单一高效构型的研发已成为新农药研发重要方向之一。介绍了氮杂环卡宾催化合成农药活性手性分子的方法及其抗细菌、真菌及病毒活性与潜在应用价值。     

具有除草活性的脲类化合物的液相合成

用苯异氰酸酯与胺反应,设计并合成了一个含除草剂敌草隆和灭草隆的２５个脲类化合物库,用含异氰酸在团或胺基团的树脂对产物进行了提纯。按组合化学中的“索引”方法,此化合物库分为１０个子库。用常规方法对１０个子库进行除草活性筛选,依据子库除草活性的顺序,重新“发现”了除草剂敌草隆和灭草隆。在新农药创制中应用这种方法,可节省时间和工作。     

具有除草活性的脲类化合物库的液相合成

用苯异氰酸酯与胺反应,设计并合成了一个含除草剂敌草隆和灭草隆的２５个脲类化合物库,用含异氰酸酯基团或胺基团的树脂对产物进行了提纯。按组合化学中的“索引”方法,此化合物库分为１０个子库。用常规方法对１０个子库进行除草活性筛选,依据子库除草活性的顺序,重新“发现”了除草剂敌草隆和灭草隆。在新农药创制中应用这种方法,可节省时间和工作。     

液相组合合成中化合物库的纯化方法研究

综述了近8年来液相组合合成中小分子化合物库的纯化方法，如通过固载化试剂的应用、可溶性聚载物的应用、氟合成技术、液相萃取等达到纯化目的。论述了这些纯化方法的基本原理、使用范围及局限，并列举了一些经典实例。     

A loop-mimetic inhibitor of the HCV-NS3 protease derived from a minibody

We have been interested for some time in establishing a strategyfor deriving lead compounds from macromolecule ligands suchas minibody variants. A minibody is a minimized antibody variabledomain whose two loops are amenable to combinatorial mutagenesis.This approach can be especially useful when dealing with `difficult'targets. One such target is the NS3 protease of hepatitis Cvirus (HCV), a human pathogen that is believed to infect about100 million individuals worldwide and for which an effectivetherapy is not yet available. Based on known inhibitor specificity(residues P6-P1) of NS3 protease, we screened a number of minibodiesfrom our collection and we were able to identify a competitiveinhibitor of this enzyme. We thus validated an aspect of recognitionby HCV NS3 protease, namely that an acid anchor is necessaryfor inhibitor activity. In addition, the characterization ofthe minibody inhibitor led to the synthesis of a constrainedhexapeptide mimicking the bioactive loop of the parent macromolecule.The cyclic peptide is a lead compound prone to rapid optimizationthrough solid phase combinatorial chemistry. We therefore confirmedthat the potential of turning a protein ligand into a low molecularweight active compound for lead discovery is achievable andcan complement more traditional drug discovery approaches.     

Managing laboratory automation: integration and informatics in drug discovery

Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.     

Solid-phase synthesis of sulfur containing heterocycles

Solid-phase organic synthesis by combinatorial techniques is a widely exploited area in the discovery of new pharmacologically active compounds and is a rapidly expanding area of synthetic organic chemistry. Because of many biological activities possessed by heterocycles, a large number of reports related to their solid-phase synthesis have appeared in recent decades. In this review article, I have described the importance of solid-phase synthetic strategies for the synthesis of sulfur atom containing heterocycles.     

合成化学新概念——组合化学

简明地介绍 2 0世纪 90年代刚刚问世的组合化学新概念以及组合合成基本方法 ,着重叙述了“一珠一肽”混合均分合成法的基本原理及其在新药合成及筛选研究中的应用 ,并对组合合成中编码技术作了初步介绍     

Applications of click chemistry in radiopharmaceutical development

Click chemistry, a concept that employs only practical and reliable transformations for compound synthesis, has made a significant impact in several areas of chemistry, including material sciences and drug discovery. The present article describes the use of click chemistry for the development of radiopharmaceuticals. Target templated in situ click chemistry was used for lead generation. The 1,2,3-triazole moiety was found to improve the pharmacokinetic properties of certain radiopharmaceuticals. The reliable Cu(I)-catalyzed click reaction was employed for radiolabeling of peptidic compounds without the need for protecting groups. In summary, the click chemistry approach for the discovery, optimization and labeling of new radiotracers, represents a very powerful tool for radiopharmaceutical development.     

Design of new catalysts for ecological high-quality transportation fuels by combinatorial computational chemistry and tight-binding quantum chemical molecular dynamics approaches

Recently, we introduced a concept of combinatorial chemistry to computational chemistry and proposed a new method called “combinatorial computational chemistry”, which enables us to perform a theoretical high-throughput screening of catalysts. In the present paper, we reviewed our recent application of our combinatorial computational chemistry approach to the design of new catalysts for high-quality transportation fuels. By using our combinatorial computational chemistry techniques, we succeeded to predict new catalysts for methanol synthesis and Fischer–Tropsch synthesis. Moreover, we have succeeded in the development of chemical reaction dynamics simulator based on our original tight-binding quantum chemical molecular dynamics method. This program realizes more than 5000 times acceleration compared to the regular first-principles molecular dynamics method. Electronic- and atomic-level information on the catalytic reaction dynamics at reaction temperatures significantly contributes the catalyst design and development. Hence, we also summarized our recent applications of the above quantum chemical molecular dynamics method to the clarification of the methanol synthesis dynamics in this review.     

Computational chemistry, data mining, high-throughput synthesis and screening - informatics and integration in drug discovery

Drug discovery today includes considerable focus of laboratory automation and other resources on both combinatorial chemistry and high-throughput screening, and computational chemistry has been a part of pharmaceutical research for many years. The real benefit of these technologies is beyond the exploitation of each individually. Only recently have significant efforts focused on effectively integrating these and other discovery disciplines to realize their larger potential. This technical note will describe one example of these integration efforts.     

Simultaneous Disulfide and Boronic Acid Ester Exchange in Dynamic Combinatorial Libraries

Dynamic combinatorial chemistry has emerged as a promising tool for the discovery of complex receptors in supramolecular chemistry. At the heart of dynamic combinatorial chemistry are the reversible reactions that enable the exchange of building blocks between library members in dynamic combinatorial libraries (DCLs) ensuring thermodynamic control over the system. If more than one reversible reaction operates in a single dynamic combinatorial library, the complexity of the system increases dramatically, and so does its possible applications. One can imagine two reversible reactions that operate simultaneously or two reversible reactions that operate independently. Both these scenarios have advantages and disadvantages. In this contribution, we show how disulfide exchange and boronic ester transesterification can function simultaneous in dynamic combinatorial libraries under appropriate conditions. We describe the detailed studies necessary to establish suitable reaction conditions and highlight the analytical techniques appropriate to study this type of system.     

The Borane Adventure — Past,Present and Future

Forty-eight years ago, diborane was a chemical rarity, available only in two laboratories in the world. The requirements of research during World War II led to the discovery of practical synthetic methods of diborane and to the discovery of sodium borohydride. These turned out to be excellent reducing agents in organic chemistry. Exploration of these reducing characteristics led to the discovery of hydroboration. Hydroboration made organoboranes readily available. These organoboranes have proven to be the most versatile intermediates now available for organic synthesis. A recent development makes possible the synthesis of essentially any compound containing a chiral center in both optical isomers in essentially 100% optical purity. Thus this research program has taken boranes from a material available only in trace quantities to a reagent widely used in organic synthesis, greatly assisting the chemist in overcoming synthetic difficulties.