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Synthesis of Confirmation-Restricted Analogs of FTY720 as Sphingosine 1-Phosphate Receptor Pro-Drugs

Huang, Tao
Format
Thesis/Dissertation; Online
Author
Huang, Tao
Advisor
McGarvey, Glenn
Macdonald, Timothy
Abstract
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. FTY720 (Fingolimod), a synthetic analog of S1P, is not only a FDA approved drug for relapsing remitting multiple sclerosis (RRMS) but also a powerful molecular tool for investigating 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 S1P 2 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. Among those synthetic analogs, VPC122096, a cyclopentyl-incorporated analog of FTY720 showed a promising potential to be an effective S1P receptor pro-drug since it is effectively and effiently phosphorylated in vivo and induces lymphopenia at pretty low dosing. To elucidate the stereochemistry-activity relationship, we developed an asymmetric 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. Two of the four isomers that are good substrates of SphKs induce lymphopenia even at dose as low as 0.1 mg/kg, which is even more potent than FTY720. ii Contents Abstract………………………………………………………………………………….…i Contents………………………………………………………………………………..….ii List of Figures…………………………………………………………………………….vi List of Schemes…………………………………………………………………………viii List of Tables…………………………………………………………………………..…ix List of Abbreviations……………………………………………………………………... Note: Abstract extracted from PDF text
Language
English
Published
University of Virginia, Department of Chemistry, PHD (Doctor of Philosophy), 2012
Published Date
2012-05-01
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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