Issue 3, 2000
From the journal:

Journal of the Chemical Society, Perkin Transactions 1

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

Neil A. Caplan,a   Christopher I. Pogson,b   David J. Hayesb  and  G. Michael Blackburna  

a Chemistry Department, University of Sheffield, Brook Hill, Sheffield, UK

b Glaxo-Wellcome, Stevenage, Hertfordshire, UK

Abstract

A series of conformationally-restrained analogues of 1,3-bisphospho-D-glyceric 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 also incorporate α-halogen substituents to make them isopolar and isosteric mimics of the natural substrate. A monocyclic aryl core between the two phosphoryl centres provides both a rigid framework linking these moieties and loci for further substitution. The compounds were tested against human 3-PGK and found to be good competitive inhibitors. α-Fluorination of the phosphonic acids increased the affinity for the enzyme into the submicromolar range. Correlation of IC50 data with pKa3 and pKa4 values indicates that the acidity of the phosphoryl group exerts a strong influence on protein binding.

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Article information

DOI
https://doi.org/10.1039/A906507E
Article type
Paper
Submitted
10 Aug 1999
Accepted
22 Nov 1999
First published
25 Jan 2000

J. Chem. Soc., Perkin Trans. 1, 2000, 421-437

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

N. A. Caplan, C. I. Pogson, D. J. Hayes and G. M. Blackburn, J. Chem. Soc., Perkin Trans. 1, 2000, 421 DOI: 10.1039/A906507E

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