Pilot-Scale Library Production Based on Phosphine Catalysis of Allenes

描述(申请人提供)：小有机分子经常被用来调节与疾病相关的蛋白质的功能，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来干扰蛋白质功能，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，生物检测中的筛选结果也可能在治疗药物中使用。如果化学遗传筛选要导致发现具有强大生理效应的新的小分子，则需要独特和多样化的小分子文库。理想情况下，一个小分子文库应该能够干扰人类的大部分蛋白质，但这个理想的化学文库目前还不存在。作为朝着这一目标迈出的一步，面向多样性的合成(DOS)已经成为一种新的范式。DOS的目标是生成一系列在三维支架上不同的小分子；然而，事实证明，获得支架多样性比创建一个来自一个支架的化合物库更具挑战性，比如在组合化学中。在该方案中，我们分析了DOS的现状，并提出了一种强大的DOS机制：组合支架。在组合支架策略中，随着反应条件数目的相加增加，实现了支架数目的倍增。为了实现组合支架，提出了膦催化的联烯酸环的开发。当对树脂结合的尿囊酸酯进行所建议的环化时，将产生一个含有53个不同支架的化合物库。由于拟议的文库中的产品至少包含一个可变取代基，该项目将产生一个文库。这些文库将提交给NIH分子文库小分子资料库(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个模型化合物。使用这些化合物的初步分析已经发现了GGTase I、FTase、PalmitoylTransfer酶和磷酸酶的小分子酶抑制剂，以及其他几种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.