Fingolimod phosphoramidate prodrugs: Synthesis, photophysical characterisation and lipid bilayer interaction of fluorescent tagged Prodrug

FTY720 (Fingolimod, Gilenya, 1), a structural analog of sphingosine (2) was the first orally administered drug approved for the treatment of multiple sclerosis (MS). However, the phosphate derivative of Fingolimod, namely Fingolimod-1-phosphate (FTY720-1P, 3) is the biologically active molecule in MS as well as in various lysosomal storage diseases such as mucolipidosis IV and Nieman-Pick. In all cases, Fingolimod requires to be phosphorylated, resembling the natural sphingosine phosphate (4), to accomplish its therapeutic/biological effects. Here, we report the synthesis of a small library of prodrugs that could provide the efficient delivery of 3, the bioactive species. Moreover, to gain insight about the biological behaviour of these novel candidates within human body such as cell and brain blood barrier penetration we have prepared and spectroscopically characterised a fluorescent tagged version of one of the new prodrugs. The behavior of our prodrugs with respect to biological membranes was evaluated by studying the interaction between the fluorescent prodrug 18 and DOPC/DPPC liposome models.