title: Design, Synthesis, and Anti-leukemic Activity of Stereochemically Defined Constrained Analogs of FTY720 (Gilenya).
abstract: FTY720 functions as an immunosuppressant due to its effect on sphingosine-1-phosphate receptors. At doses well above those needed for immunosuppression, FTY720 also has anti-neoplastic actions. Our published work suggests that at least some of FTY720's anti-cancer activity is independent of its effects on S1P receptors and due instead to its ability to induce nutrient transporter down-regulation. Compounds that trigger nutrient transporter loss but lack FTY720's S1P receptor-related, dose-limiting toxicity have the potential to be effective and selective anti-tumor agents. In this study, a series of enantiomerically pure and stereochemically diverse O-substituted benzyl ethers of pyrrolidines was generated and tested for the ability to kill human leukemia cells. The stereochemistry of the hydroxymethyl was found to be a key determinant of compound activity. Moreover, phosphorylation of this group was not required for anti-leukemic activity.
authors.affiliation: Department of Chemistry, Université de Montréal, PO Box 6128, Station Centre-Ville, Montréal, Que., H3C 3J7, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fransson
authors.forename: Alison N
authors.initials: AN
authors.lastname: McCracken
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: McMonigle
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
keywords: FTY720; arylmethyl ether; leukemia; pyrrolidine