Late-stage functionalization and bioactivity investigation of azaphilone compounds

PROPOSAL SUMMARY Traditional medicines relies on plants and fungi to provide treatments for various diseases. These treatments have withstood the test of time with active ingredients that are natural products, compounds generated by these organisms. Natural products are a successful source of inspiration for medicines and therapeutics today. However, due to the complex structures of many natural products, synthetic routes toward these compounds are often long and difficult. Thus, there is a need for new approaches to enable the synthesis of these compounds in an efficient and high throughput manner to be able to test their viability as therapeutics. One natural product class that has promise as therapeutics, but has little research due to the difficulty of synthesis, are azaphilone natural products. Azaphilones have been used in China for over 1000 years in a health food remedy call “red mold rice”. These molecules have shown antibacterial, antifungal, antiviral, anti-inflammatory, cholesterol synthesis inhibition, and cytotoxic activity. Azaphilones are a large, structurally diverse class of natural products. Development of a high throughput, efficient route to a large variety of azaphilones would enable access to potentially life-saving therapeutics. Two subclasses that are prevalent in this natural product family are dimerized and reduced azaphilones. I aim to use biocatalysis to synthesize these two subclasses of azaphilones in a high throughput manner using P450 enzymes and reductase enzymes. Once these natural products are synthesized, in combination with azaphilones I have previously made, I aim to investigate the biological activity using a fluorescence polarization assay exploring azaphilone effects on protein-protein interactions. This will impact the development of novel medicine alternatives for treating major human health concerns such as viral infections, bacterial infections, fungal infections, high cholesterol, and cancer.