Design and Synthesis of α-Bromo Phosphonates as Analogues of Glucose-6-Phosphate

Protein phosphorylation is a crucial component in physiological signal transduction pathways. It is estimated that one-third of all cellular proteins are modified through phosphorylation, and these pathways are regulated by kinase and phosphatase enzymes. Glucose-6-phosphatase (G6Pase) is an essential enzyme that catalyzes the last step in both glycogenolysis and gluconeogenesis by converting glucose-6-phosphate (G6P) into glucose. As a result, aberrant G6Pase signaling has been implicated in diabetes. The active site of G6Pase contains a nucleophilic histidine residue, and two arginine residues that stabilize binding through hydrogen bonding to the phosphate moiety. In this thesis we present novel synthetic methodology to install α-bromophosphonate moieties on G6P analogues to test as irreversible inhibitors of G6Pase, which could serve as a valuable tool in the study of glucose metabolism. We describe our efforts towards the synthesis of a panel of phosphonate-based G6P analogues which were tested for in vitro activity against the enzyme.