Topologically Unique Scaffolds in Photoassisted Diversity Oriented Synthesis (PDO

光辅助多样性定向合成（PDO）中拓扑独特的支架

• 批准号: 7939167
• 负责人: ANDREI G KUTATELADZE
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939167
• 关键词: Acetals; Adopted; Base Sequence; Biological; Chemicals; Chemistry; Combinatorial Synthesis; Generations; Goals; Light; Methodology; Methods; Molecular; Pattern; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Photochemistry; Reaction; Reagent; Sampling; Screening procedure; Structure; Therapeutic Agents; functional group; novel; pharmacophore; public health relevance; scaffold; skeletal; small molecule

DESCRIPTION (provided by applicant): The general goal of this proposal is to develop a new synthetic methodology where high yielding photochemical key reactions are incorporated into a diversity-oriented split-and-pool combinatorial synthesis. Photochemistry offers a range of spectacular skeletal transformations, yet their utilization in high throughput synthetic methods is insignificant. We aim to develop a new synthetic methodology for rapid access to topologically diverse polycyclic scaffolds decorated by various functional groups and carbo/heterocyclic pendants, rigidly or semi-rigidly held in a unique spatial configuration by this core framework. Expeditious access to such topologically diverse scaffolds will be realized via key photochemical steps and their combination with ground state reactions, most prominently - the recently discovered synthetic sequence based on photoprotolytic oxametathesis. Achieving a well-defined three-dimensional relationship within an assortment of functional groups and/or heterocyclic moieties is central to synthetic medicinal chemistry. A broad objective is to generate potential pharmacophores by systematically sampling the chemical space with diversified core structures augmented with a range of peripheral functionalities. From the high throughput chemistry standpoint this task can only be achieved with a diverse set of distinctive core scaffolds suspending a variety of functional pendants in a unique 3D pattern. Our photoprotolytic oxametathesis allows for the generation of topologically unprecedented polycyclic acetal scaffolds, rigidly displaying a variety of heterocycles in a well-defined spatial arrangement. Critical for the split-and-pool implementation of this synthetic strategy is the fact that the photoprotolytic sequence offers nearly quantitative yields. PUBLIC HEALTH RELEVANCE: Photochemical reactions initiated by light hold unparalleled promise for building unusual molecular frameworks and offer expeditious access to difficult synthetic targets. Yet, with the exception of a few landmark syntheses, synthetic organic photochemistry remains underutilized by synthetic organic chemists. This is especially true for diversity-oriented synthesis (DOS) and its split-and-pool implementation, which are most relevant to high-throughput synthesis of small molecules and discovery of new promising therapeutic agents. We are developing novel synthetic methodologies, enabling us to gain expeditious access to a massive number of new drug-like molecules, which will be available for biological screening. Not unimportant is the fact that photochemical steps use light as a reagent, and therefore could be environmentally friendly.

描述（由申请人提供）：该提案的一般目标是开发一种新的合成方法论，将高屈服的光化学关键反应纳入了面向多样性的分裂和池组合合成中。光化学提供了一系列壮观的骨骼变换，但它们在高吞吐量合成方法中的利用并不重要。 我们旨在开发一种新的合成方法，以快速访问由各种功能组和碳/杂环吊坠装饰的拓扑多样性的脚手架，该核心是用这种核心框架以独特的空间配置来固定的。迅速进入此类拓扑多样的支架将通过关键的光化学步骤及其与基态反应的结合来实现，最突出的是基于光早期溶解氧的最近发现的合成序列。 在各种官能团和/或杂环部分中建立了明确定义的三维关系是合成药物化学的核心。一个广泛的目标是通过系统地对具有多种核心结构的化学空间进行系统采样，以增加一系列外围功能。从高吞吐量化学的角度来看，只能通过各种独特的核心支架来实现此任务，这些核心脚手架会以独特的3D模式悬挂各种功能性吊坠。我们的光早期溶解氧疗法允许生成拓扑前空前的多环状支架，在明确定义的空间排列中僵硬地显示了各种异源。对于这种合成策略的分裂和池实施至关重要的是，光早期溶解序列提供了几乎定量的产量。 公共卫生相关性：Light发起的光化学反应具有无与伦比的承诺来构建异常的分子框架，并迅速访问了困难的合成目标。然而，除了一些具有里程碑意义的合成外，合成有机光化学仍然没有被合成有机化学家所利用。对于以多样性为导向的合成（DOS）及其分裂和池实施尤其如此，这与小分子的高通量合成以及发现新的有前途的治疗剂最相关。我们正在开发新型的合成方法，使我们能够迅速获取大量新药样分子，可用于生物学筛查。并不重要的是，光化学步骤使用光作为试剂，因此可能是环保的。