Pilot-Scale Library Production Based on Phosphine Catalysis of Allenes

描述（由申请人提供）：有机小分子常用于调节疾病相关蛋白的功能，从而促进和恢复人体健康。在化学遗传学方法中，小分子文库被系统地用于干扰，从而阐明蛋白质的功能。当感兴趣的蛋白质是人类疾病的原因时，从生物测定中筛选的结果也可能在治疗药物中找到它的用途。如果化学遗传筛选的结果是发现具有强大生理作用的新小分子，那么需要独特而多样的小分子文库。理想情况下，一个小分子文库应该能够扰乱人类体内的大多数蛋白质，但这种理想的化学文库目前还不存在。作为实现这一目标的一步，面向多样性的综合（DOS）已经成为一种新的范式。DOS的目标是生成一系列小分子，这些小分子在三维支架上有所不同；然而，获得支架多样性已被证明比在组合化学中创建由一个支架衍生的化合物库更具挑战性。在这个建议中，我们分析了DOS的现状，并提出了一个强大的机制：组合脚手架。在组合支架策略中，随着反应条件数量的增加，支架数量成倍增加。为了实现组合支架，提出了开发磷化氢催化的异丙酸环。当提议的环对树脂结合的烯丙酸盐进行时，将产生具有53种不同支架的化合物库。由于拟议库中的产品包含至少一个变量取代基，因此该项目将生成一个库的库。这些文库将提交给NIH分子文库小分子库（MLSMR）进行高通量生物学筛选。开发所提出的化学合成过程已经产生了171种模型化合物。使用这些化合物进行的初步分析已经发现了GGTase I、FTase、棕榈酰转移酶和磷酸酶的小分子酶抑制剂，以及其他一些具有有趣生物活性的化学物质。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.