Photochemical synthesis of bioactive molecules

项目摘要 该提案的总体主题是开发和应用新的和使能的光催化 制备能够模拟苯胺基序结构的化合物的方法通常 在药物分子中发现。这些方法在其各自的合成过程中提供了战略层面的优势。 由于广泛的官能团相容性，温和的反应条件，可扩展性和操作性， 简单性，同时在药物发现早期纳入基于代谢的设计标准 过程利用可见光的新方法是一种无毒的“试剂”，不会产生化学废物， 有吸引力的化学合成策略， 具有挑战性的起始材料制备，进一步使得能够以环境意识的方式进行合成。 该提案的主要目标是利用应变释放开环反应来制备 以前无法访问的图案，并证明它们的效用，作为替代代谢不稳定 苯胺在药物发现中的功能。具体来说，我们将利用这些化学发现来解决现代 治疗开发方面的挑战，即：1）新型KCNQ激动剂，用于满足听力障碍的未满足需求 (i.e.耳鸣;环糊精诱导的耳毒性）;和2）拉帕替尼的代谢惰性类似物， 代表癌症治疗和抗菌研究的新领导者，同时也作为生物探针， 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 在药物发现中的即时影响和多方面的应用，旨在展示 对综合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.