Asymmetric Ugi for a Diversity-Oriented Pathway

面向多样性的途径的不对称 Ugi

基本信息

批准号：
6881220
负责人：
Peter R Andreana
金额：
$ 1.72万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6881220
关键词：
Schiff bases catalyst chemical genetics chemical reaction chemical structure enzyme mechanism high performance liquid chromatography postdoctoral investigator small molecule stereoisomer

项目摘要

DESCRIPTION (provided by applicant): The identification of complex small molecules, which bind to receptors, proteins and enzymes, has been expedited through the use of combinatorial methods and the development of high throughput screening. The identified biological targets serve as powerful tools for pharmacological studies and are essential for drug development. The long term objectives of this proposed research are: to make creative contributions to the catalytic asymmetric synthesis of multicomponent coupling reactions namely the Ugi four component coupling reaction, to elucidate the general mechanism of the reaction, to develop a complex small molecule library incorporating appending processes, differentiating processes and folding processes so that from one reaction process, many different skeletal structures can be realized, and to determine the interaction that the range of compounds have on receptors, proteins and enzymes. Through the use of chiral Lewis acids, stereo-diversity will be incorporated into a tricyclic-lactam intermediate whereby building block diversity, through appending processes, will decorate this core structure. A metathesis reaction will reveal a folding process producing compounds with varying skeletal arrays. These complex small molecules will be utilized in a chemical genetics approach to perturb biological function through cytoblot assays and decipher disease pathways by utilizing the technique of high throughput screening. Both phenotypic screens and protein-binding assays will be performed to generate direct leads for drug development and cancer treatment.

描述（由申请人提供）：通过组合方法的使用和高通量筛选的发展，加速了与受体、蛋白质和酶结合的复杂小分子的鉴定。已确定的生物靶点可作为药理学研究的强大工具，对于药物开发至关重要。本研究的长期目标是：为多组分偶联反应（即 Ugi 四组分偶联反应）的催化不对称合成做出创造性贡献，阐明反应的一般机理，开发包含附加过程的复杂小分子库，区分过程和折叠过程，以便从一个反应过程中可以实现许多不同的骨架结构，并确定一系列化合物对受体、蛋白质和酶的相互作用。通过使用手性路易斯酸，立体多样性将被纳入三环内酰胺中间体中，从而通过附加过程，构建块多样性将装饰该核心结构。复分解反应将揭示产生具有不同骨架阵列的化合物的折叠过程。这些复杂的小分子将用于化学遗传学方法，通过细胞印迹分析扰乱生物功能，并利用高通量筛选技术破译疾病途径。将进行表型筛选和蛋白质结合测定，以产生药物开发和癌症治疗的直接线索。