α-Bromophosphonate analogs of glucose-6-phosphate are inhibitors of glucose-6-phosphatase

• Synthesis of an α-bromophosphonate glucoside as an analog of G6P.
• Synthesis of α,α-dibromo, and α-bromo-α,β-unsaturated glucosides.
• Glucosides containing phosphonate analogs inhibit G6Pase.

Glucose-6-phosphatase (G6Pase) is an essential metabolic enzyme that has upregulated activity in Type II diabetes. Synthetic analogs of the G6Pase substrate, glucose-6-phosphate (G6P), may provide new tools to probe enzyme activity, or lead to specific inhibitors of glycosylphosphatase enzymes. Here we have developed synthetic routes to a panel of non-hydrolyzable G6P analogs containing α-bromo, α,α-dibromo, and α-bromo-α,β-unsaturated phosphonates compatible with a carbohydrate nucleus. We confirm that these functionalities have potency as inhibitors of G6Pase in vitro, providing a series of new phosphate isosteres that can be exploited for inhibitor design.

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