Pilot-Scale Library Production Based on Phosphine Catalysis of Allenes

描述（由申请人提供）：有机小分子通常用于调节疾病相关蛋白质的功能，从而促进和恢复人类健康。 在化学遗传学方法中，小分子文库被系统地用于干扰并从而阐明蛋白质功能。 当感兴趣的蛋白质是人类疾病的原因时，在生物测定中筛选的命中也可能在治疗药物中找到它的用途。 如果化学遗传筛选导致发现具有强大生理效应的新小分子，则需要独特且多样的小分子文库。 理想情况下，一个小分子库应该能够干扰人体中的大多数蛋白质，但这种理想的化学库还不存在。 作为实现这一目标的一个步骤，多样性导向的综合（DOS）已成为一种新的范式。 DOS的目标是生成一系列在三维支架上不同的小分子;然而，获得支架多样性已被证明比创建来自一个支架的化合物库更具挑战性，如组合化学。 在这个建议中，我们分析了DOS的当前状态，并提出了一个强大的机制：组合支架。 在组合支架化策略中，支架数量的倍增增加与反应条件数量的加性增加一起实现。 为了实现组合支架，膦催化的allenoate annulations的发展提出。 当对树脂结合的丙二烯酸酯进行所提出的环化时，将产生具有53种不同支架的化合物库。 由于来自拟议库的产品含有至少一个可变取代基，因此该项目将产生一个库的库。 这些文库将提交给NIH分子图书馆小分子库（MLSMR）进行高通量生物筛选。 开发拟议的化学合成的过程已经产生了171种模型化合物。 使用这些化合物的初步试验已经发现了GGT酶I、FT酶、棕榈酰转移酶和磷酸酶的小分子酶抑制剂，以及具有有趣生物活性的几种其他化学物质。 这四种酶与多种人类疾病有关，如癌症、心脏病、糖尿病和阿尔茨海默氏症;因此，我们在最初的文库中发现的小分子配体具有重要的医学意义。

DESCRIPTION (provided by applicant): Small organic molecules are often used to modulate the function of disease-related proteins and thereby promote and restore human health. In the chemical genetics approach, libraries of small molecules are used systematically to perturb and thereby elucidate protein function. When the protein of interest is a cause for human disease, the hit from the screening in biological assays may also find its use in therapeutic remedies. If chemical genetic screens are to result in the discovery of new small molecules with powerful physiological effects, libraries of unique and diverse small molecules are desired. Ideally, a library of small molecules should be able to perturb most of the proteins in humans, but this ideal chemical library does not yet exist. As a step toward this goal, diversity-oriented synthesis (DOS) has emerged as a new paradigm. The goal in DOS is to generate an array of small molecules that differ in their three-dimensional scaffolds; however, gaining access to scaffold diversity has proven to be more challenging than creating a library of compounds derived from one scaffold, as in combinatorial chemistry. In this proposal we analyze the current state of DOS and propose a powerful mechanism for it: combinatorial scaffolding. In the combinatorial scaffolding strategy a multiplicative increase in the number of scaffolds is achieved with an additive increase in the number of reaction conditions. To achieve combinatorial scaffolding, the development of phosphine-catalyzed allenoate annulations is proposed. When the proposed annulations are performed on the resin-bound allenoates, a library of compounds with 53 different scaffolds will be generated. Since the products from the proposed library contain at least one variable substituent, the project will produce a library of libraries. These libraries will be submitted to the NIH Molecular Libraries Small-Molecule Repository (MLSMR) for high-throughput biological screening. The process of developing the proposed chemical synthesis has already produced 171 model compounds. Preliminary assays using these compounds have resulted in the discovery of small molecule enzyme inhibitors for GGTase I, FTase, palmitoyltransferase, and phosphatases, as well as several more chemicals with interesting biological activities. The four enzymes are implicated in diverse human disorders, such as cancer, heart diseases, diabetes, and Alzheimer's; therefore, the small molecule ligands we discovered in our initial library have significant medical implications.