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.
© 2019 Deutsche Pharmazeutische Gesellschaft.
MeSH terms
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Anti-Inflammatory Agents / toxicity
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Azepines / chemical synthesis*
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Azepines / chemistry
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Azepines / pharmacology
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Cell Adhesion / drug effects
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Cell Survival / drug effects
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Drug Design
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / immunology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / toxicity
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Epoxy Compounds / chemical synthesis*
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Epoxy Compounds / chemistry
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Epoxy Compounds / pharmacology
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Human Umbilical Vein Endothelial Cells
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Humans
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Molecular Docking Simulation
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Neutrophils / drug effects
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Neutrophils / immunology
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Protein Binding
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Structure-Activity Relationship
Substances
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Anti-Inflammatory Agents
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Azepines
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Enzyme Inhibitors
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Epoxy Compounds
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase 2, human