NBD-labeled derivatives of the immunomodulatory drug FTY720 as tools for metabolism and mode of action studies

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.

Graphical abstractFluorescently labeled bioactive analogs of FTY720 and its phosphate with variable aliphatic spacers between the aromatic ring and the NBD label have been synthesized. Efficient phosphorylation in vitro, in vivo as well as signaling via the S1P receptors were demonstrated for the octanyl and undecanyl derivatives.Figure optionsDownload full-size imageDownload as PowerPoint slide