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SYNTHESIS AND TESTING OF SUGAR PHOSPHOFLUORIDATES AND CYCLIC PHOSPHATES AS INHIBITORS OF PHOSPHOGLUCOMUTASE

TitleSYNTHESIS AND TESTING OF SUGAR PHOSPHOFLUORIDATES AND CYCLIC PHOSPHATES AS INHIBITORS OF PHOSPHOGLUCOMUTASE
Publication TypeJournal Article
Year of Publication1992
AuthorsPERCIVAL, MD, Withers, SG
JournalJOURNAL OF ORGANIC CHEMISTRY
Volume57
Pagination811-817
Date PublishedJAN 31
ISSN0022-3263
Abstract

Three aldose phosphofluoridates, D-glucose 6-phosphofluoridate, alpha-D-mannopyranosyl phosphofluoridate, and 2-deoxy-2-fluoro-alpha-D-glucopyranosyl phosphofluoridate, have been synthesized from the parent phosphate and 2,4-dinitrofluorobenzene, and the mechanism of fluorination has been investigated. Another modified aldose phosphate, alpha-D-glucopyranosyl 4,6-cyclic phosphate {[}phosphate] has also been synthesized as an analogue of 6-phospho-alpha-D-glucopyranosyl phosphate. These compounds were tested as possible mechanism-based inactivators of rabbit muscle phosphoglucomutase, but no time-dependent inactivation was observed. They were, however, found to be reversible inhibitors of phosphoglucomutase, and comparison of their dissociation constants with those of the parent phosphates revealed that the removal of a single negative charge weakens ground-state binding by approximately 11 kJ/mol. Further, the absence of any detectable phosphorylation of these analogues reveals that this second charge is even more important for transition-state interaction, contributing at least 40 kJ/mol to transition-state stability. This suggests that the parent substrates bind to the enzyme and react in their dianionic forms, and it provides a measure of the value of charge-charge interactions at the active site of this key metabolic enzyme.

DOI10.1021/jo00029a007