Photochemical synthesis of bioactive molecules

项目总结 这项提案的主要主题是开发和应用新的、能够实现的光催化 能够模拟通常的苯胺基序结构的化合物的制备方法 在药物分子中发现。这些方法在其各自的综合应用中提供了战略层面的优势 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 简单性，同时在药物发现的早期纳入基于新陈代谢的设计标准 进程。使用可见光的新方法是一种无毒的不会产生化学废物的“试剂”， 有吸引力的化学合成策略，避免依赖昂贵的和合成的 具有挑战性的起始材料制备，进一步使合成能够以环保的方式进行。 这项提议的主要目标是利用释放应变的开环反应来准备 以前无法获得的基序及其作为代谢性不稳定的替代品的有效性展示 药物发现中的苯胺官能化。具体地说，我们将利用这些化学发现来解决现代 治疗发展中的挑战，即：1)针对听力障碍未得到满足的需求的新型KCNQ激动剂 (即耳鸣；环糊精诱导的耳毒性)；以及2)代谢惰性的拉帕替尼类似物，它将 在癌症治疗和抗菌研究方面代表着新的领先，同时也是 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 在药物发现中的立竿见影和多方面的应用，旨在展示 对合成创新的投资可以产生广泛的影响。

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.