Journal
TETRAHEDRON
Volume 73, Issue 10, Pages 1324-1330Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2017.01.041
Keywords
Trehalose-6-phosphate phosphatase; Trehalose-6-sulfate; Fluorophosphonate; T6P analogs
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Funding
- NIH [R21 AI103484]
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In this study, trehalose 6-phosphate phosphatase (T6PP) was targeted for inhibitor development. T6PP catalyzes the hydrolysis of trehalose-6-phosphate to form trehalose and inorganic phosphate, a reaction essential to important fungal, bacterial, and nematodal pathogens. At the current time, there are no specific inhibitors of T6PP available to serve as tools for interrogating its structure and function nor as leads for pharmaceutical applications. Herein, we describe the synthesis of non-hydrolysable mimics of trehalose-6-phosphate, which incorporate 6-sulfate (1),-phosphonate (2),-fluorophosphonate (3) and boronate (4) groups in place of the 6-phosphate moiety of the substrate. The inhibitory efficacies of these adducts were evaluated against trehalose 6-phosphatephosphatases selected from evolutionarily distant pathogenic bacteria and nematodes. Phosphonates 2 and 3 were found to display good inhibitory activities against the T6PPs, while the sulfate analog, trehalose-6-sulfate, proved to be a particularly effective broad-spectrum inhibitor of these phosphatases and an ideal prototype for optimization. (C) 2017 Elsevier Ltd. All rights reserved.
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