Extended aromatic polyheterocycles via scaffold-guided photoinduced cascades

通过支架引导的光诱导级联扩展芳族多杂环

• 批准号: 10046898
• 负责人: ANDREI G KUTATELADZE
• 金额: $ 43.47万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046898
• 关键词: 3-Dimensional; Aldehydes; Architecture; Area; Biological; Biology; Chemicals; Collection; Complex; Databases; Development; Drug Design; Funding; Goals; Grant; Growth; Heterocyclic Compounds; Hydrogen; Imidazole; Imines; Institutes; Ketones; Learning; Libraries; Light; Llama; Methodology; Modernization; Molecular; Nitrogen; Organic Chemistry; Oxygen; Peripheral; Pharmaceutical Chemistry; Photochemistry; Process; Productivity; Protons; Pyrazoles; Pyrimidine; Reaction; Reagent; Research; Sampling; Structure; Students; Sulfur; Synthesis Chemistry; Time; United States National Institutes of Health; Universities; Work; base; compound 30; cycloaddition; design; drug discovery; healthy aging; in silico; innovation; method development; molecular modeling; nitrene; novel; novel therapeutics; open innovation; pharmacophore; programs; scaffold; screening; tool; training opportunity; undergraduate research

It took half a century for the CAS database to clear a symbolic milestone of 100M compounds in 2015. Only four years later, this number stands at 156M, attesting to an impressive growth of productivity in a large part driven by drug design and discovery. Yet, the rate of FDA approvals of new molecular entities, excluding the biologics, has been anemic for a long time, oscillating between 10 and 30 annually. Such a small yield was explained, in part, by the lack of truly new and complex structures in the pipeline, which in turn, could be because a very limited number of synthetic reactions happen to dominate the chemical landscape of modern medicinal chemistry. This makes new methods development critically important for synthetic chemistry. Given the recent rise of synthetic photochemistry, which is becoming a broadly accepted tool in the toolbox of organic and medicinal chemistry, our overall goal is to discover new photoinduced reactions and develop them into robust and powerful synthetic methodologies. In this proposal, we will focus our effort on three unprecedented reactions offering rapid access to aromatic polyheterocyclic molecular architectures via (i) a new photoinduced cascade initiated by the excited state proton transfer (ESIPT) with post-photochemical decarboxylative aromatization of the primary photoproducts, (ii) a new photoinduced cascade involving a 6e- electrocyclization in aromatic imines followed by a photoinduced formation of a nitrene and subsequent electrocyclization or rearrangement, and finally (iii) a new hydrogen atom transfer (HAT)-initiated photoinduced cascade leading to complex fused pyrroloquinazolinones. In the context of diversity-oriented synthesis of complex aromatic polyheterocycles, this proposal outlines a clear path to new molecular architectures occupying an unexplored or underexplored areas of chemical space. 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. Adding three new powerful photoinduced cascades to the arsenal of synthetic chemistry is innovative and impactful. With several indications of biological activity in the preliminary studies, this project will involve targeted biological screening of compounds synthesized in the course of this study. Also, as an AREA R15, this multifaceted project will provide ample training opportunities for undergraduate research students in the PI’s lab. The students will be involved with synthesis, learn photochemistry and photophysics, molecular modeling, spectra analysis and prediction, and gain initial understanding of medicinal chemistry and biological screening.

CAS 数据库花了半个世纪才清除了 1 亿种化合物的象征性里程碑 2015 年。仅仅四年后，这个数字就达到了 1.56 亿，证明了令人印象深刻的增长 然而，生产率在很大程度上是由药物设计和发现驱动的。 新分子实体的数量（不包括生物制品）长期以来一直处于贫血状态，摇摆不定 每年 10 到 30 个产量如此之低，部分原因是缺乏真正的新产品。 以及管道中的复杂结构，这可能是因为数量非常有限 合成反应恰好主导了现代药物化学的化学领域。 这使得新方法的开发对于合成化学至关重要。 鉴于合成光化学最近的兴起，它正在成为一种被广泛接受的工具 在有机化学和药物化学的工具箱中，我们的总体目标是发现新的 光诱导反应并将其发展成稳健且强大的合成方法。 根据这项提议，我们将把精力集中在三个前所未有的反应上，以提供快速获得 芳香族多杂环分子结构通过（i）引发新的光诱导级联 通过激发态质子转移 (ESIPT) 和光化学后脱羧 主要光产物的芳构化，（ii）涉及 6e- 的新光诱导级联 芳香族亚胺的电环化，然后光诱导形成氮烯和 随后的电环化或重排，最后（iii）新的氢原子转移 (HAT) 引发的光诱导级联反应产生复杂的稠合吡咯并喹唑啉酮。 在复杂芳香多杂环的多样性导向合成的背景下，该提案 概述了一条通往新分子结构的清晰道路，占据了未开发或未充分开发的领域 化学空间领域的广泛目标是通过产生潜在的药效团。 通过多样化的核心结构系统地对化学空间进行采样，并增强了 一系列外围功能。 在合成化学武器库中添加三种新的强大的光诱导级联是 初步研究表明具有创新性和影响力。 该项目将涉及在过程中对合成化合物进行有针对性的生物筛选 此外，作为 AREA R15，这个多方面的项目将提供样本培训。 为 PI 实验室的本科生提供机会 学生将参与其中。 通过合成，学习光化学和光物理学、分子建模、光谱分析 和预测，并初步了解药物化学和生物筛选。