Design, Synthesis, and Anti-leukemic Activity of Stereochemically Defined Constrained Analogs of FTY720 (Gilenya)

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Nov 26

PMID 24273632

Citations 7

Authors

Rebecca Fransson

Alison N McCracken

Bin Chen

Ryan J McMonigle

Aimee L Edinger

Stephen Hanessian

Affiliations

Soon will be listed here.

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.

Citing Articles

Dynamic Phosphoproteomics Uncovers Signaling Pathways Modulated by Anti-oncogenic Sphingolipid Analogs.

Kubiniok P, Finicle B, Piffaretti F, McCracken A, Perryman M, Hanessian S Mol Cell Proteomics. 2018; 18(3):408-422.

PMID: 30482847 PMC: 6398214. DOI: 10.1074/mcp.RA118.001053.

In search of constrained FTY720 and phytosphingosine analogs as dual acting anticancer agents targeting metabolic and epigenetic pathways.

Garsi J, Sernissi L, Vece V, Hanessian S, McCracken A, Simitian G Eur J Med Chem. 2018; 159:217-242.

PMID: 30292898 PMC: 6217821. DOI: 10.1016/j.ejmech.2018.09.043.

Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation.

McCracken A, McMonigle R, Tessier J, Fransson R, Perryman M, Chen B Leukemia. 2016; 31(3):669-677.

PMID: 27573555 PMC: 5332311. DOI: 10.1038/leu.2016.244.

The emerging role of FTY720 (Fingolimod) in cancer treatment.

White C, Alshaker H, Cooper C, Winkler M, Pchejetski D Oncotarget. 2016; 7(17):23106-27.

PMID: 27036015 PMC: 5029614. DOI: 10.18632/oncotarget.7145.

Attacking the supply wagons to starve cancer cells to death.

Selwan E, Finicle B, Kim S, Edinger A FEBS Lett. 2016; 590(7):885-907.

PMID: 26938658 PMC: 4833639. DOI: 10.1002/1873-3468.12121.

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