Pilot-Scale Library Production Based on Phosphine Catalysis of Allenes

基于丙二烯膦催化的中试规模文库生产

基本信息

批准号：
7925144
负责人：
OHYUN KWON
金额：
$ 18.64万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-04 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7925144
关键词：
Aldehydes Alkenes Alzheimer&apos s Disease Binding Biological Biological Assay Catalysis Chemicals Collection Combinatorial Synthesis Complex Coumarins Development Diabetes Mellitus Diels Alder reaction Disease Diversity Library Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Esters Generations Genetic Screening Goals Health Heart Diseases Human Imines Laboratories Libraries Ligands Maleimides Malignant Neoplasms Medical Modeling Molecular Bank Phosphines Phosphoric Monoester Hydrolases Physiological Plant Resins Process Production Proteins Pyrones Reaction Screening procedure Solid Solutions Succinimides Therapeutic United States National Institutes of Health alpha benzopyrone analog base chemical genetics chemical synthesis combinatorial combinatorial chemistry cyclohexene human disease interest novel propadiene protein function protein geranylgeranyltransferase pyrroline repository scaffold small molecule small molecule libraries

Aldehydes Alkenes Alzheimer&apos s Disease Binding Biological Biological Assay Catalysis Chemicals Collection Combinatorial Synthesis Complex Coumarins Development Diabetes Mellitus Diels Alder reaction Disease Diversity Library Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Esters Generations Genetic Screening Goals Health Heart Diseases Human Imines Laboratories Libraries Ligands Maleimides Malignant Neoplasms Medical Modeling Molecular Bank Phosphines Phosphoric Monoester Hydrolases Physiological Plant Resins Process Production Proteins Pyrones Reaction Screening procedure Solid Solutions Succinimides Therapeutic United States National Institutes of Health alpha benzopyrone analog base chemical genetics chemical synthesis combinatorial combinatorial chemistry cyclohexene human disease interest novel propadiene protein function protein geranylgeranyltransferase pyrroline repository scaffold small molecule small molecule libraries

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项目摘要

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.

描述（由申请人提供）：小有机分子通常用于调节与疾病相关蛋白的功能，从而促进和恢复人类健康。在化学遗传学方法中，小分子的文库系统地用于干扰，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，生物测定中筛查的命中也可能会发现其在治疗疗法中的使用。如果化学遗传筛选会导致发现具有强大生理效应的新小分子，则需要具有独特和多样的小分子的库。理想情况下，小分子的库应该能够扰动人类中的大多数蛋白质，但是这个理想的化学库尚不存在。为了朝着这一目标迈出一步，以多样性为导向的合成（DOS）已成为一种新的范式。 DOS的目标是产生一系列在三维脚手架上不同的小分子。但是，事实证明，获得脚手架多样性的访问比在组合化学中像创建一个脚手架的化合物库更具挑战性。在此建议中，我们分析了DOS的当前状态，并提出了一种强大的机制：组合脚手架。在组合脚手架策略中，随着反应条件数量增加，脚手架数量的乘法增加。为了实现组合脚手架，提出了磷酸催化的艾龙酸盐环境的发展。当对树脂结合的艾龙群落进行提出的环境时，将生成一个具有53个不同脚手架的化合物库。由于拟议库中的产品至少包含一个可变取代基，因此该项目将生产一个库库。这些文库将提交给NIH分子库小分子存储库（MLSMR），以进行高通量生物学筛查。开发提出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测定导致发现了针对GGTase I，FTase，Palmitoyltransferase和磷酸酶的小分子酶抑制剂，以及更多具有有趣生物学活性的化学物质。这四种酶与多种人类疾病有关，例如癌症，心脏病，糖尿病和阿尔茨海默氏症。因此，我们在初始文库中发现的小分子配体具有重大的医学意义。