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，其中高产量光化学钥匙反应被纳入面向多样性的分裂和池组合合成中。光化学反应具有建立复杂多环子支架的无与伦比的承诺。他们为复杂的合成目标提供了许多合成快捷方式和简洁的途径。然而，光化学从未成为合成化学家及其利用中的一种追求的工具高通量合成根本不存在。具体而言，我们旨在开发一种新的光助手合成方法，以快速访问拓扑多样性的N，O，S-聚coly型环含量很大一部分SP3杂交碳原子和立体中心，由各种功能组和用独特的空间配置牢固地固定或半二合一的碳/杂环吊坠这些新型的核心框架具有最少的可旋转键。合成策略将涉及关键的光化学步骤及其与基态反应的结合，大多数明显地，我们最近发现的圆锥形苯甲酸苯甲酸苯甲酸苯甲酸苯甲酸苯甲酸苯通过激发状态质子从氨基或氨基群转移到羰基的光生成组或亚胺。在各种功能中建立了明确的三维关系组和/或杂环部分是合成药物化学的核心。宽阔目的是通过系统地采样化学物质来产生潜在的药剂团具有多元化核心结构的空间增强了一系列外围功能。从高吞吐量的化学角度来看，只能通过多样化来实现此任务独特的核心支架，以独特的3D模式悬挂了各种功能性吊坠。高通量合成方法被指责为“转向发现的努力，芳香化合物“虽然天然产物具有广泛的生物活性，但没有什么比SP2主导的芳香杂环。我们的光助手合成方法学将产生各种含有高的独特（聚）杂环核心支架饱和的数量，即SP3，由Lovering的FSP3饱和参数量化的碳。