High-throughput chemoenzymatic synthesis of bioactive compounds

生物活性化合物的高通量化学酶合成

基本信息

批准号：
10218074
负责人：
Joshua Pyser
金额：
$ 0.69万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-19 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218074
关键词：
Acylation Amines Anti-Bacterial Agents Antifungal Agents Benign Biological Biological Assay Carbon Case Study Cells Chemicals Complex Coupling Data Development Drug resistance Enzymes Exhibits Flavins Fluorescence Polarization Generations Health Hepatocyte Individual Infection Investigation Lead Libraries Ligands Link Literature Malignant Neoplasms Mediating Methodology Methods Mixed Function Oxygenases Natural Products Nature Oxidants Pharmaceutical Preparations Pharmacologic Substance Phenotype Physical condensation Pigments Positioning Attribute Process Production Property Reaction Research Personnel Resources Route Site Speed Structure Structure-Activity Relationship Students System Therapeutic Time TimeLine Work analog anticancer activity base catalyst chemical reaction combat design drug discovery halogenation high throughput screening next generation non-alcoholic fatty liver disease novel novel therapeutics scaffold small molecule

项目摘要

Proposal Summary With drug-resistant infections and cancers becoming more prominent, it is crucial to investigate new classes of small molecules to combat these growing health crises. Azaphilones, an underexplored class of fungal natural products, have been shown to exhibit diverse biological properties, making them candidates as a novel class of therapeutics. Although preliminary studies demonstrate their utility in this regard, further investigation of their activities has been hindered due to the challenges of constructing their densely functionalized core and congested stereocenter. Furthermore, selectively accessing either C7 configuration of these scaffolds presents an addition hurdle to exploring azaphilone structure-activity relationships. The most concise approach toward this class of molecules relies on the oxidative dearomatization of prefunctionalized arenes. Current state-of-the-art methods in asymmetric oxidative dearomatization require superstoichiometric quantities of both an oxidant and expensive chiral ligand. These methods have also only been demonstrated on a limited substrate scope, can exhibit poor site-selectivity, and require forcing reaction conditions. Fortunately, Nature has evolved superior catalysts to perform oxidative dearomatization with greater site- and stereoselectivity than these established chemical methods. Promisingly, we have identified two flavin- dependent monooxygenase homologs, AzaH and AfoD, which can perform an oxidative dearomatization on aromatic substrates with the same site-selectivity, but provide the opposite stereochemical configuration in the subsequent azaphilone product. This pivotal discovery enables their use in the synthesis of various natural products and synthetic building blocks, providing orthogonal site- and stereoselectivity to more readily access greater chemical space in an environmentally-benign manner. Furthermore, these catalysts can operate mild reaction conditions, making them compatible with high-throughput compound generation platforms. This proposal describes strategies for the use of these biocatalysts in stereodivergent, chemoenzymatic syntheses for the rapid generation of azaphilone analogs. In summary, this work aims to investigate azaphilone structure-activity relationships through high-throughput and strategic diversification of these scaffolds, directed by a fluorescence polarization assay and a cell painting screen. The methods established herein will provide a means to efficiently develop increasingly potent azaphilone-based drugs.

提案摘要随着耐药感染和癌症变得越来越突出，研究新的类别至关重要小分子以应对这些日益增长的健康危机。 Azaphilones，一类不受欢迎的真菌天然产品已被证明具有多种生物学特性，使它们成为新颖的一类疗法。尽管初步研究证明了它们在这方面的效用，但进一步研究了他们由于构建其密集功能化的核心和拥挤的立体中心。此外，选择性访问这些脚手架的C7配置探索Azaphilone结构活性关系的额外障碍。这类分子的最简洁方法依赖于氧化的亲爱的人预官能化领域。不对称氧化的最新方法需要氧化剂和昂贵的手性配体的超恒星计量量。这些方法也只有在有限的底物范围上证明，可以表现出较差的位点选择性，并且需要强迫反应状况。幸运的是，自然已经进化了上催化剂，以更大的位置和立体选择性比这些已建立的化学方法。有希望的是，我们已经确定了两种黄素 - 依赖性单加氧化酶同源物，azah和afod，可以在具有相同位点选择性的芳族底物，但在随后的Azaphilone产品。这个关键发现使它们可以在综合各种自然的综合中使用产品和合成的构件，提供正交的站点和立体选择性，以便更容易访问以环保方式更大的化学空间。此外，这些催化剂可以轻微起作用反应条件，使其与高通量复合生成平台兼容。这提案描述了在立体化学化学合成中使用这些生物催化剂的策略用于快速的阿扎菲酮类似物。总而言之，这项工作旨在通过高通量和这些脚手架的战略多样化，由荧光极化测定和细胞绘画指导屏幕。本文建立的方法将提供一种有效发展越来越有效的方法基于阿扎菲酮的药物。