Synthesis and Biological Evaluation of Sphingosine Kinase 2 Inhibitors With Anti-Inflammatory Activity

Arch Pharm (Weinheim). 2019 Mar;352(3):e1800298. doi: 10.1002/ardp.201800298. Epub 2019 Jan 16.

Abstract

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.

Keywords: anti-inflammatory activity; bioassays; molecular modeling; sphingosine kinase 2 inhibitors; synthesis.

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / toxicity
  • Azepines / chemical synthesis*
  • Azepines / chemistry
  • Azepines / pharmacology
  • Cell Adhesion / drug effects
  • Cell Survival / drug effects
  • Drug Design
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • Epoxy Compounds / chemical synthesis*
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Molecular Docking Simulation
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Azepines
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase 2, human