Phosphate Isosteres in Medicinal Chemistry

Abstract

The phosphate group is at the heart of an enormous number of biological processes. The simple phosphorylation or dephosphorylation of a protein can have a wide range of consequences, including effects on its biological activity, its interaction with other proteins, and on its subcellular location. Abnormal levels of protein phosphorylation have been linked to a wide range of diseases including cancer and diabetes. Consequently, proteins that recognise the phosphate moiety have become an attractive target for therapeutic development. The most prevalent medicinal chemistry research examines the interactions of phosphorylated tyrosine residues; however, the role of phosphate groups on serine or threonine residues, in nucleotides, DNA and RNA, on sugars, and lipid mediators such as lysophosphatidic acid should not be overlooked. Investigations have focused on the non-catalytic phosphotyrosine-recognising domains such as Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, as well as catalytic proteins such as protein tyrosine phosphatase 1B (PTP1B). The utilisation of the phosphate moiety as part of an inhibitor is severely limited by the enzymatic lability and poor cellular bioavailability of this highly charged recognition element. The development of phosphate isosteres attempts to address these issues by introducing a non-scissile bond and utilizing groups with less charge that are still able to interact favourably with the target protein in much the same way as the phosphate group does. Many phosphate mimics retain the phosphorus atom such as in the highly successful fluoromethylenephosphonates, whereas others have lost the tetrahedral phosphate geometry and are based on the combination of one or more carboxylate groups that generally reduce the overall charge of the molecule. This review focuses on the recent developments and the use of phosphate isosteres in medicinal chemistry, covering roughly the past four years.

Insights into the Reaction of Protein-tyrosine Phosphatase 1B

“…A common strategy is focused on the synthesis of competitive inhibitors that block the active site (6,11,14). Binding affinities in these cases range from millimolar to micromolar, and specificity is often compromised by the high similarity between PTP active sites.…”

Synthesis and Biological Activity of Metabolically Stabilized Cyclopentyl Trisphosphate Analogues of D‐myo‐Ins(1,4,5)P3

“…[7] We describe herein the preparation of four analogues of the parent trisphosphate 2. We also present evaluation of ligand binding to the InsP 3 R using a fluorescence resonance energy transfer method, and we use computational algorithms to dock the synthetic analogues into the type I InsP 3 R.…”

Synthesis of arabinose glycosyl sulfamides as potential inhibitors of mycobacterial cell wall biosynthesis

“…Besides the arabinose monosaccharide, DPA contains both a highly polar and labile glycosyl phosphate and a long hydrophobic polyprenol side chain. One may postulate that effective and stable mimics of DPA should therefore contain both a suitable isosteric replacement for the phosphate, 9 and a hydrophobic side chain. Significant work on the synthesis of mimics of DPA has already been reported, for example by Lowary, 7c-e including the synthesis of β-C-glycosyl sulfones 10 and C-phosphonates of arabinofuranose.…”