Synthesis of phosphonates and bisphosphonates as potential therapeutics

Phosphorus-based pharmaceutical agents have been explored for decades and successfully utilized to treat a variety of diseases. The phosphonate is a common scaffold used due to its increased metabolic stability compared to phosphates. Phosphonates can be designed to target the isoprenoid biosynthetic pathway. This metabolic pathway leads to the production of an immensely diverse variety of biomolecules including sterols, vitamins, hormones, and other aspects of cellular metabolism. The isoprenoid biosynthetic pathway has been connected to a wide range of cancers and disorders. To combat this, the enzymes of this pathway have been scrutinized as targets for therapeutic agents. Phosphoantigens are small-molecule organophosphorus compounds that are recognized by a subset of immune cells that express the γδ T cell receptor. The T cell population quickly expands after detecting exogenous phosphoantigens from bacterial infections. These cells also recognize endogenous phosphoantigens, and thus play a critical role in cancer immunosurveillance. Although there are significant gaps in our understanding of the mechanism of phosphoantigen-induced T cell proliferation, it is understood that phosphoantien binding to an intracellular domain of the butyrophilin 3A1 protein is necessary for any γδ T cell response. To probe critical protein interactions, an extensive structure-activity relationship study of phosphonates derived from the microbial phosphoantigen HMBPP have been synthesized. Recent contributions to this project include the development of a synthetic double prodrug approach, which focuses primarily on the efficacy of cell-cleavable allylic acetate moieties on the phosphoantigen payload. Another avenue of investigation is the synthesis of fluorescence quenching phosphoantigen prodrugs that can provide insight on spatiotemporal activation of the phosphoantigen payload by plasma esterases.