Photoassisted access to novel polyheterocyclic scaffolds with increased saturatio

光辅助获得饱和度增加的新型多杂环支架

• 批准号: 8626881
• 负责人: ANDREI G KUTATELADZE
• 金额: $ 33.05万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626881
• 关键词: Aging; Aldehyde-Lyases; Amidone; Aromatic Compounds; Biological; Biological Factors; Carbon; Chemicals; Chemistry; Collaborations; Combinatorial Synthesis; Complex; Crimean Hemorrhagic Fever; Deubiquitinating Enzyme; Development; Enzymes; Fructose; Furans; Generations; Imines; Libraries; Light; Methodology; Methods; Molecular; Motivation; Mycobacterium tuberculosis; Nitrogen; Oxygen; Pathway interactions; Pattern; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Photochemistry; Protease Domain; Protons; Pyrroles; Reaction; Reagent; Research; Research Institute; Robotics; Sampling; Solid; Structure; Sulfur; Therapeutic Agents; Thiophenes; United States National Institutes of Health; Universities; Viral; amino group; carbonyl group; combinatorial; cycloaddition; diketopiperazine; functional group; inhibitor/antagonist; inorganic phosphate; novel; ovarian neoplasm; pharmacophore; programs; public health relevance; scaffold; screening; small molecule; tool

We will develop a new synthetic methodology where high yielding photochemical key reactions are incorporated into a diversity-oriented split-and-pool combinatorial synthesis. Photochemical reactions hold unparalleled promise for building complex polycyclic scaffolds. They offer a number of synthetic shortcuts and concise pathways to complex synthetic targets. Yet, photochemistry never became a sought-after tool by synthetic chemists and its utilization in high-throughput synthesis is simply non-existent. Specifically, we aim to develop a new photoassisted synthetic methodology for rapid access to topologically diverse N,O,S-polyheterocycles, containing a large fraction of sp3 hybridized carbon atoms and stereogenic centers, and decorated by various functional groups and carbo/heterocyclic pendants rigidly or semi-rigidly held in a unique spatial configuration by these novel core frameworks with a minimal number of rotatable bonds. The synthetic strategy will involve key photochemical steps and their combination with ground state reactions, most prominently our recently discovered intramolecular cycloadditions of azaxylylenes photogenerated via excited state proton transfer from the amido or amino-group to the carbonyl group or imine. Achieving a well-defined three-dimensional relationship within an assortment of functional groups and/or heterocyclic moieties is central to synthetic medicinal chemistry. The 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. High throughput synthetic methods are blamed for "steering discovery efforts toward achiral, aromatic compounds" while natural products, possessing a broad spectrum of bioactivity, look nothing like the sp2-dominated aromatic heterocycles. Our photoassisted synthetic methodology will produce a variety of unique (poly)heterocyclic core scaffolds containing high number of saturated, i.e. sp3, carbons quantified by Lovering's Fsp3 saturation parameter.

我们将开发一种新的合成方法，其中高产的光化学关键 反应被纳入到面向多样性的分裂池组合合成中。 光化学反应在构建复杂的多环支架方面有着无与伦比的前景。 它们为复杂的合成目标提供了大量的合成捷径和简明的途径。 然而，光化学从未成为合成化学家追捧的工具，并将其用于 高通量合成根本不存在。 具体地说，我们的目标是开发一种新的光辅助合成方法，以快速获得 拓扑结构多样的N，O，S-多杂环，含有较大比例的Sp3杂化 碳原子和立体中心，并由各种官能团和 碳/杂环吊坠刚性或半刚性地保持在独特的空间构型中 这些新颖的核心框架具有最少数量的可旋转键。综合战略 将涉及关键的光化学步骤及其与基态反应的结合，大多数 突出的是我们最近发现的氮杂亚甲基的分子内环加成反应 通过激发态质子从氨基或氨基转移到羰基而产生的光 团体或亚胺。 在各种功能组件中实现定义明确的三维关系 基团和/或杂环基团是合成药物化学的核心。《博大》 目的是通过系统地对化学物质进行采样来产生潜在的药效团 空间具有多样化的核心结构，并增加了一系列外围功能。 从高通量化学的观点来看，这项任务只能通过不同的集合来完成 独特的核心支架，以独特的3D图案悬挂各种功能吊坠。 高通量的合成方法被指责为“将发现努力转向非手性， 芳香化合物“，而天然产物，具有广泛的生物活性，看起来 与sp2占主导地位的芳香族杂环不同。我们的光辅助合成 方法学将生产各种独特的(多)杂环核心支架，含有高 由Lovering的Fsp3饱和度参数量化的饱和碳数，即Sp3。