Phosphonate derivatives of tetraazamacrocycles as new inhibitors of protein tyrosine phosphatases

Org Biomol Chem. 2015 Jul 21;13(27):7437-44. doi: 10.1039/c5ob00713e.

Abstract

α,α-Difluoro-β-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPβ. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemistry
  • Inhibitory Concentration 50
  • Kinetics
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Models, Molecular
  • Phosphorous Acids / chemical synthesis
  • Phosphorous Acids / chemistry*
  • Protein Tyrosine Phosphatases / antagonists & inhibitors*
  • Protein Tyrosine Phosphatases / metabolism

Substances

  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Macrocyclic Compounds
  • Phosphorous Acids
  • phosphonic acid
  • cyclam
  • Protein Tyrosine Phosphatases