Our review on synthetic medicinal chemistry of phosphotyrosine analogues and phosphomimetics is now published in RSC Medicinal Chemistry

  • ToC graphics
  • Fig. 1 Structural basis of molecular recognition specificity of pY-reader domain interactions.
  • Fig. 2 Commercially available phosphotyrosine (A) and phosphonodifluoromethyl phenylalanine (F2pmp) (B)-based building blocks.
  • Scheme 1 Synthetic strategies for the synthesis of phosphotyrosine. Available methods to synthesize a pY building block are shown.
  • Fig. 3 Cyclosaligenyl phosphotyrosine mimetic targeting SAP–SLAM interactions.
  • Scheme 2 Site-selective phosphorylation of a tyrosine-containing peptide.
  • Fig. 4 Recent applications and advances in the phosphoramidite approach.
  • Scheme 3 Novel one-pot synthesis of Fmoc-Tyr(PO(OBzl)OH)-OH.
  • Fig. 5 Aminophosphoryl chloride approach in phosphotyrosine synthesis.
  • Fig. 6 Recent applications of the dialkyl phosphite approach. A) PTP activity-based probes.
  • Scheme 4 Lewis acid catalysed tyrosine phosphorylation with pyrophosphates.
  • Scheme 5 Palladium-catalyzed mono-arylation of the β-methyl group of alanine.
  • Scheme 6 Synthetic strategies to the phosphonodifluoromethyl phenylalanine.
  • Fig. 7 Recent application of F2Pmp in drug design.
  • Fig. 8 Recent advances in the F2Pmp synthesis.
  • Fig. 9 Benzoylphosphonates as phosphotyrosine mimetics.

Congratulations to Nikolai on this comprehensive timely review. Hope people find this useful! 

Read the Open Access full article here.

Authors: Nikolai Makukhin and Alessio Ciulli*

Title: Recent advances in synthetic and medicinal chemistry of phosphotyrosine and phosphonate-based phosphotyrosine analogues

Abstract:

Phosphotyrosine-containing compounds attract significant attention due to their potential to modulate signalling pathways by binding to phospho-writers, erasers and readers such as SH2 and PTB domain containing proteins. Phosphotyrosine derivatives provide useful chemical tools to study protein phosphorylation/dephosphorylation, and as such represent attractive starting points for the development of binding ligands and chemical probes to study biology, and for inhibitor and degrader drug design. To overcome enzymatic lability of the phosphate group, physiologically stable phosphonate-based phosphotyrosine analogues find utility in a wide range of applications. This review covers advances over the last decade in the design of phosphotyrosine and its phosphonate-based derivatives, highlights the improved and expanded synthetic toolbox, and illustrates applications in medicinal chemistry.