The chemical synthesis of metabolically stabilized 2-OMe-LPA analogues and preliminary studies of their inhibitory activity toward autotaxin

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2698-700. doi: 10.1016/j.bmcl.2012.03.008. Epub 2012 Mar 10.

Abstract

The chemical synthesis of five new metabolically stabilized 2-OMe-LPA analogues (1a-e) possessing different fatty acid residues has been performed by phosphorylation of corresponding 1-O-acyl-2-OMe-glycerols which were prepared by multistep process from racemic glycidol. The now analogues were subjected to biological characterization as autotaxin inhibitors using the FRET-based, synthetic ATX substrate FS-3. Among tested compounds 1-O-oleoyl-2-OMe-LPA (1e) appeared to be the most potent, showing ATX inhibitory activity similar to that of unmodified 1-O-oleoyl-LPA. Parallel testing showed, that similar trend was also observed for corresponding 1-O-acyl-2-OMe-phosphorothioates (2a-e, synthesized as described by us previously). 1-O-oleoyl-2-OMe-LPA (1e) was found to be resistant toward alkaline phosphatase as opposed to unmodified 1-O-oleoyl-LPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lysophospholipids / chemical synthesis*
  • Lysophospholipids / chemistry
  • Lysophospholipids / pharmacology*
  • Methylation
  • Molecular Structure
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrophosphatases / antagonists & inhibitors

Substances

  • 1-O-oleoyl-2-OMe-lysophosphatidic acid
  • Enzyme Inhibitors
  • Lysophospholipids
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Pyrophosphatases