The biochemistry of phosphonate analogues of naturally occurring phosphates.

Abstract

6,7 dideoxy-alpha-D-gluco-heptose 7-phosphonic acid, the isosteric phosphonate analogue of naturally-occurring glucose 6-phosphate was synthesised via a novel route, involving the use of an easily-prepared and stable ethyl ester, followed by a facile dealkylation procedure. 6,7 dideoxy alpha-D-gluco-heptose 7-phosphonic acid was shown to behave as a product inhibitor of purified bovine brain hexokinase I, being a competitive inhibitor of MgATP2- and a noncompetitive inhibitor of glucose. 6,7 dideoxy alpha-D-gluco-heptonic 7-phosphonic acid, the isoteric phosphonate analogue of gluconate 6-phosphate was enzymically synthesised from 6,7 dideoxy alpha-D-gluco heptose 7-phosphonic acid and was shown to be a poor substrate for yeast gluconate 6-phosphate dehydrogenase at pH 7.5 and 8.0. 6,7 dideoxy alpha-D-gluco-heptose 7-phosphonic acid had no effect on cell proliferation of mouse lymphoma cells (at mM concentrations) but was found to be more stable then the natural phosphate in their presence. alpha-D-glucose fluorophosphate was tested as an active-site-directed irreversible inhibitor of yeast glucose 6-phosphate dehydrogenase with a view to eventual use of the corresponding phosphonate analogue in similar systems. The fluorophosphate was found to be inactive in this respect.

Date of Award	1980
Original language	English
Awarding Institution	University of Bath