title: NBD-labeled derivatives of the immunomodulatory drug FTY720 as tools for metabolism and mode of action studies.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1230 Vienna, Austria. peter.ettmayer@vie.boehringer-ingelheim.com
authors.forename: Peter
authors.initials: P
authors.lastname: Ettmayer
authors.forename: Thomas
authors.initials: T
authors.lastname: Baumruker
authors.forename: Danilo
authors.initials: D
authors.lastname: Guerini
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Peter
authors.initials: P
authors.lastname: Nussbaumer
authors.forename: Markus B
authors.initials: MB
authors.lastname: Streiff
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
mesh_terms: 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
chemical_list: 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