Cat. No. Name Size Price Add Cart
KI0429FTY720100 mg$190
FTY720200 mg$332

Chemical Characteristic

Product NameFTY720
SynonymsFingolimod, Gilenya
CAS No.162359-56-0
Molecular Weight 343.9
FormulaC19H33NO2.HCl
Chemical Name2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride
SmilesC(C(CO)(CCc1ccc(cc1)CCCCCCCC)N)O Cl
Chemical Structure

Biological activities

FTY720 is an antagonist of sphingosine-1-phosphate (S1P) and cannabinoid receptor , and also can specificly inhibits cPLA2 and ceramide synthase. FTY720 is derived from myriocin, used to treat multiple sclerosis as an immunomodulating drug. Phosphoryl metabolite of FTY720 and the lysophospholipid sphingosine-1-phosphate (S1P) can alter lymphocyte trafficking. FTY720 is a high-affinity agonist of at least four of the five S1P receptors and produces lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen.[1] The IC50s of FTY720 are 13, 12, 14 and 60 μM against HepG2, Huh-7, Hep3B and MIHA cells, respectively. The percentages of apoptotic nuclei are 8, 17.5, 35 and 48 at 4, 8, 16 and 24 hours, respectively, at the IC50 dose.[2] FTY720 inhibits the binding of the CB1-selective ( a subtype of cannabinoid receptors) antagonist [3H] SR141716A and the cannabinoid agonist [3H] CP55,940 in a concentration-dependent manner ( 0.01-10 μM) in both CB1-expressing cell lines and mouse cerebellum. However, FTY720 does not significantly alter [3H] CP55,940 binding to CB2 receptors (another subtype of cannabinoid receptors).[3] FTY720 (400 and 800 pmol) significantly inhibits cPLA2 activity (400 pmol 1-palmitoyl-2-[14C]-arachidonyl-sn-glycerol-phosphatidylcholine as substrate) in mast-cell lysates and reduces cPLA2 activity in RBL-2H3 or HEK 293 cells pretreated with FTY720 in the presence of saturating [Ca2+] and 150 mM NaCl. FTY720 significantly inhibits cPLA2 activity of about 50% at equimolar concentrations of cPLA2 substrate and FTY720 (1:1), and increases to 65% inhibition when the ratio of FTY720 to substrate is 2:1. Furthermore, 3 mol% FTY720 has maximal inhibition of cPLA2α activity with an IC50 of 1.1 mol%.[4] In vitro kinetic studies, FTY720 has an apparent Ki of 2.15 μM as a competitive inhibitor of ceramide synthase 2 toward dihydrosphingosine. FTY720 up-regulates dihydrosphingosine 1-phosphate (DHS1P) level through sphingosine kinase1 (SphK1), but not SphK2.[5] In vivo experiments, 3 mg/kg FYT720 reduces total lymphocyte numbers to an average of 64% with T-cells lowered by 85% and B-cells lowered by 53% and 0.3 mg/kg FTY720 decreases the total lymphocyte numbers to about 78%, the T-cell numbers to 92%, and B-cell numbers to 77% in both Sphk1 null and WT mice.[6] In the nude mouse tumor model, FTY720 (10 mg/kg) significantly suppresses tumor growth and decreases AktSer473 in Hep3B-bearing nude mice, together with an increased amount of cleaved caspase-3 and caspase-9 in a time-dependent manner.[2]

References

[1] Mandala S, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002, 296(5566): 346-349.
[2] Lee TK, et al. FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. Carcinogenesis. 2004, 25(12): 2397-2405.
[3] Paugh SW, et al. Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor. Mol Pharmacol. 2006, 70(1): 41-50.
[4] Payne SG, et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood. 2007, 109(3): 1077-1085.
[5] Berdyshev EV, et al. FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. J Biol Chem. 2009, 284(9): 5467-77.
[6] Allende ML et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem. 2004, 279(50): 52487-52492.

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