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

基本信息

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
项目类别：
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

项目摘要

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，其中高产光化学关键反应被纳入面向多样性的分流组合合成中。光化学反应对于构建复杂的多环支架具有无与伦比的前景。它们提供了许多合成捷径和简洁的途径来实现复杂的合成目标。然而，光化学从未成为合成化学家追捧的工具及其在其他领域的应用高通量合成根本不存在。具体来说，我们的目标是开发一种新的光辅助合成方法，以快速获取拓扑多样化的 N,O,S-多杂环，含有大部分 sp3 杂化碳原子和立构中心，并被各种官能团和碳/杂环吊坠刚性或半刚性地保持在独特的空间配置中这些新颖的核心框架具有最少数量的可旋转键。综合策略将涉及关键的光化学步骤及其与基态反应的结合，大多数值得注意的是我们最近发现的亚二甲苯基的分子内环加成通过从酰胺基或氨基到羰基的激发态质子转移产生光生基团或亚胺。在各种功能中实现明确定义的三维关系基团和/或杂环部分是合成药物化学的核心。广义的目标是通过系统地对化学物质进行采样来产生潜在的药效团具有多样化核心结构的空间，并增加了一系列外围功能。从高通量化学的角度来看，这项任务只能通过多样化的组合来实现独特的核心支架以独特的 3D 图案悬挂各种功能吊坠。高通量合成方法被指责为“将发现工作转向非手性、芳香族化合物”，而天然产物则具有广泛的生物活性，看起来与以 sp2 为主的芳香杂环完全不同。我们的光辅助合成该方法将产生各种独特的（多）杂环核心支架，含有高通过 Lovering 的 Fsp3 饱和参数量化的饱和碳数（即 sp3）。