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更加突出，研究新类别的药物至关重要小分子来应对这些日益严重的健康危机。 Azaphilones，一类尚未开发的天然真菌产品已被证明表现出多种生物特性，使其成为一类新型的候选产品疗法。尽管初步研究证明了它们在这方面的实用性，但进一步研究它们由于构建其密集功能化核心的挑战和拥挤的立体中心。此外，选择性地访问这些支架的任一 C7 配置呈现探索阿扎菲酮结构-活性关系的另一个障碍。此类分子最简洁的方法依赖于氧化脱芳构化预官能化芳烃。目前最先进的不对称氧化脱芳构化方法需要超化学计量的氧化剂和昂贵的手性配体。这些方法也仅已在有限的底物范围内得到证明，可能表现出较差的位点选择性，并且需要强制反应状况。幸运的是，大自然已经进化出优异的催化剂，可以以更大的速度进行氧化脱芳构化。位点选择性和立体选择性优于这些已建立的化学方法。有希望的是，我们已经鉴定出两种黄素- 依赖的单加氧酶同系物 AzaH 和 AfoD，可以对芳香族底物具有相同的位点选择性，但提供相反的立体化学构型随后的阿扎菲酮产品。这一关键发现使得它们能够用于合成各种天然物质产品和合成构件，提供正交位点和立体选择性，以便更容易访问以环境友好的方式扩大化学空间。此外，这些催化剂可以温和地运行反应条件，使其与高通量化合物生成平台兼容。这提案描述了在立体发散、化学酶合成中使用这些生物催化剂的策略用于快速生成阿扎菲酮类似物。总之，这项工作旨在通过高通量和高通量研究阿扎菲酮的结构-活性关系。通过荧光偏振测定和细胞涂色指导这些支架的战略多样化屏幕。本文建立的方法将提供一种有效开发日益有效的方法基于阿扎菲酮的药物。