Exploration of α-aminophosphonate N-derivatives as novel, potent and selective inhibitors of protein tyrosine phosphatases

Eur J Med Chem. 2012 Mar:49:354-64. doi: 10.1016/j.ejmech.2012.01.038. Epub 2012 Jan 24.

Abstract

Seventeen α-aminophosphonates are synthesized. Their compositions and structures are established by EA, UV, FT-IR, (1)H NMR, (13)C NMR, (31)P NMR and ESI-MS. Compounds 1-4 are confirmed by X-ray crystallography. PTP inhibition shows compounds 1-5, 12, 15 are moderate competitive inhibitors with some selectivity. The most potent inhibitor is compound 5 with the lowest IC(50) value about 6.64 μM against PTP1B, about 2-fold and 25-fold stronger than against TCPTP and PTP-MEG2 while it doesn't inhibit SHP-1 and SHP-2. The binding constant of 5 to PTP1B is 2.23 × 10(5) M(-1) and binding ratio approximates 1:1. Cell viability and apoptosis assays indicate 5 is cell permeable with lower cytotoxicity. The results indicate α-aminophosphonates are possibly developed to effective and selective inhibitors of PTPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology
  • Apoptosis / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology*
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / metabolism*

Substances

  • Amines
  • Enzyme Inhibitors
  • Organophosphonates
  • Protein Tyrosine Phosphatases