The synthesis of novel bisphosphonates as inhibitors of phosphoglycerate kinase (3-PGK)

A series of conformationally-restrained analogues of 1,3-bisphospho-D-glyce ric acid (1,3-BPG) 1 has been synthesised for use as inhibitors of 3-PGK (E .C. 2.7.2.3). These compounds have non-scissile phosphonate linkages and al so incorporate alpha-halogen substituents to make them isopolar and isoster ic mimics of the natural substrate. A monocyclic aryl core between the two phosphoryl centres provides both a rigid framework linking these moieties a nd loci for further substitution. The compounds were tested against human 3 -PGK and found to be good competitive inhibitors. alpha-Fluorination of the phosphonic acids increased the affinity for the enzyme into the submicromo lar range. Correlation of IC50 data with pK(a3) and pK(a4) values indicates that the acidity of the phosphoryl group exerts a strong influence on prot ein binding.