Sphingosine-1-phosphate (S1P) is a signaling lipid molecule, which has been implicated in a wide variety of biological processes including cell growth regulation, apoptotic suppression, invasion, angiogenesis and vascular maturation, immune cell migration and so forth. FTY720 (Fingolimod), a synthetic analog of S1P, is not only a FDA approved drug for relapsing remitting multiple sclerosis (RRMS) but also an important tool molecule to investigate the biology of S1P receptors and related enzymes, sphingosine kinase (SphKs) for example. It turned out that phosphorylated FTY720 by SphK2 in vivo is a low-nanomolar agonist of all the S1P receptors except S1P2 and induces lymphopenia by sequestering lymphocytes into the secondary lymphoid tissues, which is a novel mechanism different from that of those classic immunosuppressive agents.In this presentation, we will show the synthesis and biological evaluation of a library of conformationally constrained analogs of FTY720. Some of those compounds are great substrates for SphK1 or SphK2 (much better than FTY720), and induce lymphopenia at low doses. VPC122096, for example, is a cyclopentyl-incorporated analog of FTY720 and show a promising potential to be an effective S1P receptor pro-drug since it is effectively and effiently phosphorylated in vivo and induces lymphopenia.To elucidate the stereochemistry-activity relationship, we developed the chemical synthesis to access all of the four stereoisomers with high optical purity. Each stereoisomer was tested individually for the SphKs activity and lymphopenia induction. It turns out that the configuration of one chiral carbon is critical for the enzyme recognition while the other is not. And the two isomers that are good substrates of SphKs induce lymphopenia even at dose as low as 0.1 mg/kg, which is the same, if not more, potent as FTY720

Design, synthesis and biological evaluation of comformation restricted analogs of FTY720

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.