GREAT EXPECTATIONS: PHOSPH(ON)ATE PRODRUGS IN DRUG DESIGN—OPPORTUNITIES AND LIMITATIONS

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil the active pharmacophore. A secondary and conventionally overlooked function of prodrugs is their ability to mediate cell- and tissue-specific drug localization. This arises from the intrinsically different enzymatic expression or environmental conditions specific to certain cell or tissue types. Here, I explore the challenges associated with phosph(on)ate prodrugs at the synthetic, in vitro, and in vivo levels first through the lens of a phosphonate-containing enolase inhibitor and then more broadly to other phosphate prodrugs such as cyclophosphamide, sofosbuvir, and remdesivir. The findings of this work have resulted in 1.) the development of a novel phosph(on)ate amidation reaction, 2.) the discovery of a novel promoiety, 3.) the synthesis of novel enolase inhibitor prodrugs with diverse mechanisms of bioactivation, and 4.) ongoing efforts to advance the parent nucleoside of remdesivir to the clinic for the treatment of COVID-19. Together, this work epitomizes the necessity of considering model-specific limitations at the in vitro and in vivo levels for successful implementation of prodrugs in the clinic