Selective inhibition of Trypanosoma brucei GAPDH by 1,3-bisphospho-D-glyceric acid (1,3-diPG) analogues

Various phosphono-phosphates and diphosphonates were synthesized as 1,3-dip hosphoglycerate (1,3-diPG) analogues by using a beta -ketophosphonate, an a lpha -fluoro,beta -ketophosphonate or a beta -ketophosphoramidate to mimic the unstable carboxyphosphate part of the natural substrate. The inhibitory effect of these analogues on glyceraldehyde-3-phosphate dehydrogenases (GA PDH) from Trypanosoma brucei (Tb) and rabbit muscle were measured with resp ect to both substrates, glyceraldehyde-3-phosphate (GAP) and 1,3-diPG. Inte restingly, all 1,5-diphosphono,2-oxopentanes without substitution at the C- 3 position selectively inhibit the Tb GAPDH with respect to 1,3-diPG and ar e without effect on Rm GAPDH. All 1-phospho,3-oxo,4-phosphonobutanes show t hemselves to be non-selective inhibitors either with regard to substrates o r organisms, but they will be of a great interest as 1,3-diPG stable models for structural studies of co-crystals with GAPDHs. (C) 2001 Elsevier Scien ce Ltd. All rights reserved.