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

• Published in: Carbohydrate research 2013-11, Vol.381, p.123-132
• Main Authors: Downey, A. Michael, Cairo, Christopher W.
• Format: Article
• Language: English
• Subjects: Dose-Response Relationship, Drug; enzyme activity; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; glucose 6-phosphate; glucose-6-phosphatase; Glucose-6-phosphatase (G6Pase); Glucose-6-Phosphatase - antagonists & inhibitors; Glucose-6-Phosphatase - metabolism; Glucose-6-phosphate (G6P); Glucose-6-Phosphate - chemical synthesis; Glucose-6-Phosphate - chemistry; Glucose-6-Phosphate - pharmacology; Molecular Structure; Non-hydrolyzable phosphate isostere; noninsulin-dependent diabetes mellitus; Organophosphonates - chemistry; phosphates; phosphonates; Structure-Activity Relationship; α-Bromophosphonate
• ISSN: 0008-6215; 1873-426X
• DOI: 10.1016/j.carres.2013.08.003

•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.