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.
This proposal details the development of fundamentally new chemical reactions in the area of visible light photocatalysis with broad impacts on human health. These new chemical reactions provide facile and practical access to compounds of interest to medicinal chemists with specific applications in the development of novel therapies to treat multiple conditions, ranging from common hearing disorders to breast cancer.