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100m化合物的象征性里程碑 在2015年。仅四年后，这个数字为1.56亿，证明了令人印象深刻的增长 由药物设计和发现驱动的很大一部分的生产力。但是，FDA批准的速度 不包括生物制剂的新分子实体已经被动画了很长时间，振荡 每年10至30之间。由于缺乏真正的新作用，部分解释了如此小的收益 管道中的复杂结构又可能是因为数量非常有限 合成反应占据了现代医学化学的化学景观。 这使得新方法的发展对于合成化学至关重要。 鉴于合成光化学的最新兴起，这正在成为广泛接受的工具 在有机和医学化学的工具箱中，我们的总体目标是发现新的 照片诱导的反应并将其发展为强大而强大的合成方法。在 这项建议，我们将精力集中在三种前所未有的反应上，从而迅速获得 通过（i）启动的新照片诱导的级联 通过激发状态质子转移（ESIPT），具有后化学后脱羧 主要光产物的芳香化，（ii）一种新的光诱导的级联反应，涉及6e- 芳香胺的电囊肿化，然后是硝基的光诱导形成 随后的电气环化或重排，最后（iii）新的氢原子转移 （帽子）引发的光诱导的级联反应导致复杂的融合吡咯烷唑啉酮。在 复杂的芳族多元核的多样性综合的背景，该建议 概述了通往新分子体系结构的清晰途径，该结构占据了意想不到的或未经忽视的途径 化学空间区域。广泛的目标是通过 系统地以多元化的核心结构来对化学空间进行采样 外围功能范围。 在合成化学的武器库中添加三个新的强大的光诱导的级联 创新且有影响力。在初步研究中有几种迹象表明生物学活性， 该项目将涉及对在此过程中合成的化合物的有针对性的生物学筛选 这项研究。此外，作为R15区域，这个多面项目将提供足够的培训 PI实验室中的本科生研究专业的机会。学生将参与 通过合成，学习光化学和光体物理学，分子建模，光谱分析 和预测，并获得对医学化学和生物学筛查的初步理解。