Discovery and mechanistic study of fluorine biochemistry

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DESCRIPTION (Provided by the applicant) Abstract: Fluorinated pharmaceuticals represent a rapidly expanding class of small molecule drugs that have become important in the treatment of diverse human health conditions ranging from cancer to high cholesterol. Owing to its unique chemical properties, functionalization of molecules with fluorine has allowed chemists to rationally tune the bioactivity and pharmacokinetics of small molecules and turn a lead compound into an effective treatment. However, these same chemical properties limit our ability to specifically incorporate fluorine into molecules and consequently our ability to fully exploit the potential that fluorine provides as a design element in the pipeline of drug design and discovery. Although much interest has focused on new synthetic methods to make carbon-fluorine bonds, fluorination remains a challenging chemical problem with regard to specificity and selectivity. Our group is exploring the ability of living systems to incorporate fluorine into small molecules with specificity, with the long-term goal of developing alternative synthetic biology approaches for the design and production of novel fluorinated natural products. Towards this goal, we have focused on studying Streptomyces cattleya, the only known native organofluorine-producing organism, to develop a basic picture of how living systems have evolved to manage this unique element. With a more fundamental understanding of fluorine biochemistry in hand, we can begin to expand the narrow scope of fluorine biochemistry in nature and work towards developing new methods for drug design and discovery. Public Health Relevance: Fluorinated small molecules have been tapped relatively recently as a class of compounds with great utility in treating diverse conditions in human health, such as cancer, bacterial and fungal infections, depression, allergies, and high cholesterol. Indeed over half of the top five drugs sold in the last year contain fluorine. The long-term goal of our proposed work is to expand methods used to incorporate fluorine into new small-molecule compounds using biological approaches that are complementary to more traditional chemical methods.