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.
Ettmayer
Peter
P
Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1230 Vienna, Austria. peter.ettmayer@vie.boehringer-ingelheim.com
Baumruker
Thomas
T
Guerini
Danilo
D
Mechtcheriakova
Diana
D
Nussbaumer
Peter
P
Streiff
Markus B
MB
Billich
Andreas
A
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008246:Lysophospholipids / Q000737:chemistry; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008956:Models, Chemical; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry; D011409:Propylene Glycols / Q000494:pharmacology*; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D011994:Recombinant Proteins / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013379:Substrate Specificity; D013997:Time Factors; D000099157:Sphingosine Kinase
D002118:Calcium; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010069:Oxadiazoles; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; D013110:Sphingosine; D000099157:Sphingosine Kinase; C011514:4-nitrobenzofurazan