Asymmetric Ugi for a Diversity-Oriented Pathway

描述（由申请人提供）：通过使用组合方法和高通量筛选的发展，已经加速了与受体，蛋白质和酶结合的复杂小分子的鉴定。确定的生物靶点是药理学研究的有力工具，对药物开发至关重要。这项拟议研究的长期目标是：对催化不对称合成多组分偶联反应即Ugi四组分偶联反应作出创造性贡献，阐明该反应的一般机理，建立包含附加过程、分化过程和折叠过程的复杂小分子文库，从而在一个反应过程中实现许多不同的骨架结构；并确定各种化合物对受体，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，通过附加工艺，构建块多样性将修饰该核心结构。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被利用在化学遗传学方法中，通过细胞试验来扰乱生物功能，并利用高通量筛选技术来破译疾病途径。表型筛选和蛋白质结合分析将为药物开发和癌症治疗提供直接线索。

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.