DEVELOPMENT OF HETEROCYCLIC & SMALL MOLECULE ORGANIC COMBINATORIAL LIBRARIES

这个项目的中心目标是增加射程， 基于混合的合成组合的曲目和易用性 图书馆。使用精心配制的化合物混合物使 及时、经济地识别大多数客户的有效线索 生物检测。所有的库都将在位置扫描中生成 格式化。位置扫描反褶积过程，也是在 首席调查员的实验室，允许最活跃的化学物质 待鉴定分子每个位置的基团(S)直接从 初步筛查数据。将使用两种综合策略来 扩大图书馆的多样性。因此，具体目标1将基于 “从图书馆到图书馆”的方法，在校长 研究人员的实验室，用于转化现有的多肽， 多肽和杂环组合文库进入新的 通常具有完全不同的物理化学性质的多样性 相对于原始库。这种化学修饰，包括 还原、氧化、烷基化、脱水、环化等 允许生成双环胍、环脲、 海因、吲哚咪唑、多胺、羟胺、亚硝胺、 如具体目标2所述，第二个战略将涉及 组合法分步固相合成新的药物载体 格式。这些将包括硫吗啉酮类化合物的生成， 喹唑烷酮和二氮卓类药物。中描述的化学变化 具体目标1，以及固相合成新技术的发展 杂环化合物的路线(在特定目标2中描述)将 不断扩大可供筛选的化合物的多样性 程序。尤其是这种新事物产生的驱动力 图书馆将主要侧重于项目三和项目四的需要。 除了上面提到的单体化合物文库，特定的 目标3将讨论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-取代哌嗪、聚3-取代哌嗪以及 这两者的结合。这些聚合物化合物文库将是 在项目II、III和IV中进行筛选。化学物质的多样性 建议开发的结构，以及大量的 对于每一类结构的化合物，预计都会大幅增加 识别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.