DEVELOPMENT OF HETEROCYCLIC & SMALL MOLECULE ORGANIC COMBINATORIAL LIBRARIES

该项目的中心目标是增加射程， 库，并易于使用的混合为基础的合成组合 图书馆.使用精心制备的化合物混合物使得能够实现 及时和经济地识别大多数 生物测定所有的库都将在位置扫描中生成 格式.位置扫描反褶积过程，也是在1989年开发的。 首席研究员的实验室允许最活跃的化学物质 在分子的每个位置上的一个或多个基团直接从 初步筛选数据。两种合成策略将用于 扩大图书馆的规模。因此，具体目标1将基于 “图书馆中的图书馆”方法，在校长 研究者实验室，用于现有肽的转化， 肽模拟物和杂环组合文库， 通常具有完全不同的物理化学性质的二聚体 相对于原始图书馆。这些化学修饰，包括 还原、氧化、烷基化、脱水、环化等，将 允许产生双环胍，环脲， 乙内酰脲，吲哚咪唑，多胺，羟胺，亚硝胺， 等如具体目标2所述，第二项战略将涉及 组合法中新药效团固相分步合成 格式.这些将包括硫代吗啉酮，苯乙烯， 喹唑啉酮类和二氮杂类。中描述的化学变化 具体目标1，以及新的固相合成的开发 杂环化合物的路线（具体目标2中所述）将 不断扩大可用于筛选的化合物的种类 程序.特别是，这种新的生产的驱动力 图书馆将主要侧重于项目III和IV的需要。 除了上面提到的单体化合物文库之外， 目标3将解决非天然聚合物组合的发展 图书馆.这些将首先需要制备聚1，2-二酮 3-取代的哌嗪，聚3-取代的哌嗪，以及 这两者的结合。这些聚合物化合物库将是 在项目II、III和IV中筛选。化学物质的多样性 拟议开发的结构，以及大量的 化合物的每一类结构，预计将大大增加 鉴定具有潜在活性的高活性化合物的可能性 治疗效用

The central objective of this project is to increase the range, repertoire, and ease of use of mixture-based synthetic combinatorial libraries. The use of carefully prepared mixtures of compounds enable the timely and economical identification of active leads in the majority of bioassays. All of the libraries will be generated in positional scanning format. The positional scanning deconvolution process, also developed in the Principal Investigator's laboratory, allows the most active chemical group(s) at each position of the molecule to be identified direct from the initial screening data. Two synthetic strategies will be used for expanding the library diversities. Thus, Specific Aim 1 will be based on the "libraries from libraries" approach, developed in the Principal Investigator's laboratory, for the transformation of existing peptide, peptidomimetic, and heterocyclic combinatorial libraries into new diversities often having completely different physicochemical properties relative to the original libraries. Such chemical modifications, including reduction, oxidation, alkylation, dehydration, cyclization, etc., will allow the generation of libraries of bicyclic guanidines, cyclic ureas, hydantoins, indole imidazoles, polyamines, hydroxylamines, nitrosamines, etc. As described in Specific Aim 2, the second strategy will involve the step-wise solid phase synthesis of new pharmacophores in combinatorial formats. These will include the generation of thiomorpholinones, stryl quinazolinones, and diazepines. The chemical alterations described in Specific Aim 1, as well as the development of new solid phase synthetic routes to heterocyclic compounds (described in Specific Aim 2) will continually expand the diversities of compounds available for screening programs. In particular, the driving force for the generation of such new libraries will be primarily focused on the need for projects III and IV. In addition to the monomeric compound libraries mentioned above, Specific Aim 3 will address the development of non-natural polymeric combinatorial libraries. These will initially entail the preparation of poly 1,2-diketo 3-substituted piperazines, poly 3-substituted piperazines, as well as a combination of these two. These polymeric compound libraries will be screened in Projects II, III, and IV. The diversity of the chemical structures proposed for development, as well as the large number of compounds for each class of structures, is expected to greatly increase the probability of identifying highly active compounds having potential therapeutic utility.