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）：该提案的总体目标是开发一种新的合成方法，其中将高产率光化学关键反应纳入面向多样性的分流和池组合合成中。光化学提供了一系列引人注目的骨骼转变，但它们在高通量合成方法中的利用微不足道。 我们的目标是开发一种新的合成方法，用于快速获得由各种官能团和碳/杂环吊坠装饰的拓扑多样化的多环支架，并通过该核心框架刚性或半刚性地保持在独特的空间配置中。通过关键的光化学步骤及其与基态反应的结合，可以快速获得这种拓扑多样化的支架，最突出的是最近发现的基于光质子氧化氧复分解的合成序列。 在各种官能团和/或杂环部分中实现明确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对化学空间进行系统采样来生成潜在的药效团，其中化学空间具有多样化的核心结构，并具有一系列外围功能。从高通量化学的角度来看，这项任务只能通过一组不同的独特核心支架来实现，这些支架以独特的 3D 模式悬挂各种功能悬垂物。我们的光质子氧化氧复分解可以生成拓扑上前所未有的多环缩醛支架，在明确的空间排列中严格地展示各种杂环。对于这种合成策略的拆分和合并实施的关键是光质子分解序列提供了几乎定量的产率。 公共健康相关性：由光引发的光化学反应对于构建不寻常的分子框架具有无与伦比的前景，并提供快速获得困难合成目标的途径。然而，除了一些具有里程碑意义的合成之外，合成有机光化学仍未被合成有机化学家充分利用。对于面向多样性的合成（DOS）及其拆分和池实现尤其如此，这与小分子的高通量合成和新的有前途的治疗剂的发现最相关。我们正在开发新的合成方法，使我们能够快速获得大量新的类药分子，这些分子将可用于生物筛选。并非不重要的事实是，光化学步骤使用光作为试剂，因此可能是环境友好的。