Abstract
Fluorescently labeled chiral analogs of the immunomodulatory drug FTY720 and its corresponding phosphates with variable aliphatic spacers between the aromatic ring and the NBD label have been synthesized. Determining the influence of the spacer on the in vitro phosphorylation rate by SPHK1 and 2 resulted in the identification of NBD-(R)-AAL 1c,d which are phosphorylated with an efficiency comparable to that of the unlabeled FTY720 analog (R)-AAL. Furthermore, the NBD-(R)-AAL phosphates 10c,d were proven to be a functional S1P receptor agonist.
MeSH terms
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Calcium / metabolism
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Cell Line
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Cells, Cultured
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Dose-Response Relationship, Drug
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Fingolimod Hydrochloride
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Flow Cytometry
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Humans
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Immunosuppressive Agents / pharmacology*
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Lysophospholipids / chemistry
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Chemical
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / chemistry
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Propylene Glycols / pharmacology*
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Protein Binding
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Receptors, Lysosphingolipid / agonists
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Recombinant Proteins / chemistry
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Sphingosine / analogs & derivatives*
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Sphingosine / chemistry
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Sphingosine / pharmacology
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Substrate Specificity
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Time Factors
Substances
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Immunosuppressive Agents
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Lysophospholipids
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Oxadiazoles
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Propylene Glycols
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Receptors, Lysosphingolipid
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Recombinant Proteins
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4-nitrobenzofurazan
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Fingolimod Hydrochloride
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Sphingosine
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Calcium