Novel and Diverse Pilot-Scale Library Production (RMI)

描述（由申请人提供）：根据RFA-RM-05-014，我们计划使用固相和溶液相策略合成几个中试规模的文库，并提交给NIH，用于随后的各种生物检测。我们的目标是制备化学纯净、结构多样的小分子化合物。这些小分子化合物将通过改编已发表的合成路线或适当地通过开发新的合成策略来制备。面向多样性的合成（DOS）文库通常有~100-200个成员，每个成员的纯度为=90%的非商业小分子。我们的计划是为每个支架准备两种类型的库：(i)一个小型演示库，用于测试化学和验证程序，使用IRORI系统进行化合物合成和跟踪；（ii）基于Trident或irri的文库，以提供集中的化合物文库。库(i)和库（ii）的输出将被合并、存档并供生化评价使用。二硝基二氟苯基支架的制备将会越来越多、越来越多。一些固相合成文库将产生一个内置的亲水处理与特定位点的官能团，以便这些化合物可以随后标记为特定的分析，而其他将没有任何处理制备。每个化合物将用高效液相色谱法分析其纯度，并通过质谱法确认其身份。如果需要，FlashTube先进的闪蒸色谱将用于化合物纯化。NIH的PubChem将用于管理我们的各种试点图书馆，我们计划建立一个加州大学戴维斯分校的组合化学网站，链接到PubChem。根据RFA的要求，每个库成员的至少10mg将被存档，并且每个库成员的纯度为90%。

DESCRIPTION (provided by applicant): In response to the RFA-RM-05-014, we plan to use both solid- and solution-phase strategies to synthesize several pilot-scale libraries to be submitted to NIH for subsequent distribution for various biological assays. Our aim is to prepare chemically pure, structurally diverse small-molecule compounds. These small-molecule compounds will be prepared by adaptation of published synthetic routes or, as appropriate, by development of novel synthetic strategies. Diversity-oriented synthesis (DOS) libraries will generally have ~100-200 members each with =90% purity of non-commercial small-molecules. Our plan is to prepare two types of libraries for each scaffold: (i) a small demo library to test the chemistry and validate the procedures, using the IRORI system for compound synthesis and tracking; (ii) a Trident- or IRORI-based library to deliver a focused library of compounds. The output of libraries (i) and (ii) will be combined, archived, and made available for biochemical evaluation. The dinitrodifluorobenzene-based scaffold will be prepared in larger number and quantity. Some of the solid-phase synthesis libraries will be generated with a built-in hydrophilic handle with site-specific functional groups so that these compounds can be subsequently tagged for specific assays while others will be prepared without any handle. Each compound will be analyzed by HPLC for purity and its identity confirmed by mass spectroscopy. If needed, FlashTube advanced flash chromatography will be used for compound purification. The NIH PubChem will be used for management of our various pilot libraries and we plan to set up a UC Davis Combinatorial Chemistry web site with links to PubChem. As required by the RFA, at least 10 mg of each library member will be archived and each will have =90% purity.