Photochemical synthesis of bioactive molecules

生物活性分子的光化学合成

基本信息

批准号：
10252005
负责人：
Corey Stephenson
金额：
$ 41.49万
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：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252005
关键词：
Acrylamides Address Agonist Amines Aniline Antineoplastic Agents Antiparasitic Agents Area Biological Biological Assay Cations Cell-Mediated Cytolysis Cells Chemicals Clinic Conscious Creativeness Cyclodextrins Development Discipline ERBB2 gene Electrophysiology (science)Engineering Ensure Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluation Family Generations Goals Health Hearing problem Hepatotoxicity Human Individual Investigation Investments Ion Channel Libraries Malignant Neoplasms Mediating Metabolic Metabolism Methods Modernization Molecular Niemann-Pick Diseases Nitrogen Oncology Patients Pharmaceutical Preparations Phosphotransferases Photochemistry Positioning Attribute Preparation Prevention Process Property Quinazolines Reaction Reagent Research Risk Factors Role Science Site Structure Therapeutic Intervention Tinnitus Toxic effect Translating Ursidae Family Variant Visible Radiation analog antimicrobial base cancer therapy chemical reaction chemical synthesis cycloaddition design drug discovery functional group high risk immunogenicity innovation interest lapatinib malignant breast neoplasm neglected tropical diseases novel novel therapeutics ototoxicity patch clamp scaffold therapeutic development wasting

项目摘要

PROJECT SUMMARY The overarching theme of this proposal is the development and application of new and enabling photocatalytic methods for the preparation of compounds capable of mimicking the structure of aniline motifs commonly found in drug molecules. These approaches provide strategy-level advantages in their respective synthetic applications due to broad functional group compatibility, mild reaction conditions, scalability, and operational simplicity while simultaneously incorporating metabolism-based design criteria early in the drug discovery process. New methods using visible light, a non-toxic 'reagent' that does not generate chemical waste, are attractive strategies for chemical synthesis circumventing the reliance upon expensive and synthetically challenging starting material preparation, further enabling synthesis in an environmentally conscious fashion. The major goals of this proposal leverage strain-releasing ring-opening reactions for the preparation of previously inaccessible motifs and the demonstration of their utility as replacements of metabolically-labile aniline functionality in drug discovery. Specifically we will leverage these chemical findings to address modern challenges in therapeutic development, namely: 1) novel KCNQ agonists for unmet needs in hearing disorders (i.e. tinnitus; cyclodextrin-induced ototoxicity); and 2) metabolically-inert analogs of lapatinib which will represent new leads in cancer therapy and antimicrobial research while also serving as biological probes for studying the immunogenicity of hepatotoxic drugs.. These goals translate creativity in reaction science into immediately-impactful and multi-faceted applications in drug discovery and are intended to demonstrate the broad-reaching influence that can arise from investment in synthetic innovation.

项目概要该提案的首要主题是新型光催化材料的开发和应用通常能够模拟苯胺基序结构的化合物的制备方法发现于药物分子中。这些方法在各自的合成中提供了策略级优势由于广泛的官能团兼容性、温和的反应条件、可扩展性和可操作性而得到广泛应用简单性，同时在药物发现早期纳入基于代谢的设计标准过程。使用可见光的新方法是一种不会产生化学废物的无毒“试剂” 有吸引力的化学合成策略，避免对昂贵和合成的依赖具有挑战性的起始材料制备，进一步以环保的方式实现合成。该提案的主要目标是利用应变释放开环反应来制备以前无法获得的主题及其作为代谢不稳定的替代品的实用性的展示药物发现中的苯胺功能。具体来说，我们将利用这些化学发现来解决现代问题治疗开发中的挑战，即： 1) 新型 KCNQ 激动剂，用于满足听力障碍方面未满足的需求（即耳鸣；环糊精引起的耳毒性）； 2) 拉帕替尼的代谢惰性类似物，它将代表了癌症治疗和抗菌研究的新领先，同时也可作为生物探针研究肝毒性药物的免疫原性。这些目标将反应科学的创造力转化为在药物发现中具有立即影响力和多方面的应用，旨在证明对综合创新的投资可以产生广泛的影响。