FTY720 (S)-Phosphate ((S)-FTY720P)
(Synonyms: （S）FTY720磷酸盐,(S)-FTY720P; (S)-FTY720 phosphate) 目录号 : GC31736
Analog of S1P
Cas No.:402616-26-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | Mice[1]Male C57BL/6 (20-25 g) mice 8-10 weeks old receive a single intratracheal dose of bleomycin at 0.6 U/kg (or sterile saline) on Day 0 followed immediately by intraperitoneal injection of FTY720 (S)-Phosphate (0.5 mg/kg), FTY720 (0.5 mg/kg), or saline. Additional doses of FTY720 (S)-Phosphate or FTY720 are injected on Days 3 and 6. Bronchoalveolar lavage (BAL) fluid and lungs are then collected on Day 7. BAL fluid is used to detect BAL protein levels, WBC count, and WBC differential count. Lungs are perfused with saline to remove blood for Western blot, tissue albumin, and histopathology evaluation. Peripheral blood is obtained on Day 7 for examination of total cell counts and lymphocytes. Experiments are repeated 3 times. 6-10 mice are used per experimental group[1]. |
References: [1]. Wang L, et al. FTY720 (s)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and exhibits superior barrier protection to FTY720 in acute lung injury. Crit Care Med. 2014 Mar;42(3):e189-99. | |
FTY720 is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs.1 FTY720 is phosphorylated by sphingosine kinases in vivo, and then acts as a potent agonist at four of the five sphingosine-
1.Brinkmann, V., Pinschewer, D.D., Feng, L., et al.FTY720: Altered lymphocyte traffic results in allograft protectionTransplantation72(5)764-769(2001) 2.Brinkmann, V., Davis, M.D., Heise, C.E., et al.The immune modulator FTY720 targets sphingosine 1-phosphate receptorsJ. Biol. Chem.277(24)21453-21457(2002) 3.Albert, R., Hinterding, K., Brinkmann, V., et al.Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomerJ. Med. Chem.48(16)5373-5377(2005) 4.Kiuchi, M., Adachi, K., Tomatsu, A., et al.Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphateBioorg. Med. Chem.13(2)425-432(2005) 5.Brinkmann, V.FTY720: Mechanism of action and potential benefit in organ transplantationYonsei Med. J.45(6)991-997(2004) 6.Honig, S.M., Fu, S., Mao, X., et al.FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodesJ. Clin. Invest.111(5)627-637(2003) 7.Payne, S.G., Oskeritizian, C.A., Griffiths, R., et al.The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptorsBlood109(3)1077-1085(2007)
| Cas No. | 402616-26-6 | SDF | |
| 别名 | （S）FTY720磷酸盐,(S)-FTY720P; (S)-FTY720 phosphate | ||
| Canonical SMILES | OC[C@](CCC1=CC=C(CCCCCCCC)C=C1)(N)COP(O)(O)=O | ||
| 分子式 | C19H34NO5P | 分子量 | 387.45 |
| 溶解度 | Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C,unstable in solution, ready to use. |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.581 mL | 12.9049 mL | 25.8098 mL |
| 5 mM | 0.5162 mL | 2.581 mL | 5.162 mL |
| 10 mM | 0.2581 mL | 1.2905 mL | 2.581 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Structural insights into sphingosine-1-phosphate receptor activation
Proc Natl Acad Sci U S A.2022 Apr 19;119(16):e2117716119.PMID:35412894DOI: 10.1073/pnas.2117716119.
As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs.
Structure-function analysis of lipid substrates and inhibitors of sphingosine kinases
Cell Signal.2020 Dec;76:109806.PMID:33035646DOI: 10.1016/j.cellsig.2020.109806.
The sphingosine kinases, SK1 and SK2, catalyse the formation of the bioactive signalling lipid, sphingosine 1-phosphate (S1P), from sphingosine. SK1 and SK2 differ in their subcellular localisation, trafficking and regulation, but the isoforms are also distinct in their selectivity toward naturally occurring and synthetic ligands as substrates and inhibitors. To date, only the structure of SK1 has been determined, and a structural basis for selectivity differences in substrate handling by SK2 has yet to be established. Here we present a structural rationale, based on homology modelling and ligand docking, to account for the capacity of SK2, but not SK1, to efficiently process the pharmacologically active substances, fingolimod (FTY720) and safingol, as substrates. We propose that two key residue differences in hSK2 (Ser305/Thr584 in place of Ala175/Ala339 in hSK1) facilitate conformational switching in the lipid head group anchor residue, Asp308 (corresponding to Asp178 in hSK1), to accommodate substrate diversity for SK2. Our analysis accounts for the contrasting behaviour of fingolimod and safingol as non-turnover inhibitors of SK1, but substrates for SK2, and the observed stereoselectivity for phosphorylation of the pro-S hydroxymethyl group of fingolimod to generate (S)-FTY720-P in vivo. We also rationalise why methylation of the pro-R hydroxymethyl of FTY720 switches the behaviour of the resulting compound, (R)-FTY720 methyl ether (ROMe), to SK2-selective inhibition. Whilst the pharmacological significance of (S)-FTY720-P is firmly established, as the active principle of fingolimod in treating relapsing-remitting multiple sclerosis, the potential importance of SK-mediated phosphorylation of other substrates, such as safingol and non-canonical naturally occuring substrates such as (4E,nZ)-sphingadienes, is less widely appreciated. Thus, the contribution of SK2-derived safingol 1-phosphate to the anti-cancer activity of safingol should be considered. Similarly, the biological role of sphingadiene 1-phosphates derived from plant-based dietary sphingadienes, which we also show here are substrates for both SK1 and SK2, merits investigation.
Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus
Cell Mol Immunol.2006 Feb;3(1):11-9.PMID:16549044
Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism(s) of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I (myriocin). FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P] by sphingosine kinase 2 in vivo. (S)-FTY720-P acting as a potent agonist of S1P receptor type 1 (S1P1), induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite (S)-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.
FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration
Cell Mol Immunol.2005 Dec;2(6):439-48.PMID:16426494
FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4(+) T cells into spinal cord was decreased by prophylactic treatment with FTY720 and (S)-FTY720-P. When FTY720 or (S)-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-beta, and the area of demyelination and the infiltration of CD4(+) T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4(+) T cells into the inflammation site.
Novel immunomodulators based on an oxazolin-2-one-4-carboxamide scaffold
Bioorg Med Chem Lett.2012 Jan 1;22(1):553-7.PMID:22119341DOI: 10.1016/j.bmcl.2011.10.088.
A series of oxazolidin-2-one-4-carboxylic amide compounds (1a-f) were designed and synthesized as the non-phosphate S1P(1) receptor agonists. The single crystal of 1e was prepared and solved to elucidate the structure of 1a-f. EC(50) of 1a-d were about 1.1-3.6 μM in S1P(1) Redistribution® assay, and their cytotoxicity was 8-40-fold lower than FTY720. Though its S1P(1) agonist activities in vitro were about 1000-folds weaker than (S)-FTY720-P, at a dose of 10mg/Kg, the immunosuppressive effects of 1a were comparable to FTY720. So oxazolidin-2-one-4-carboxylic amide derivatives were found as potential immunomodulator, compound 1a could be considered as a lead compound, rational modifications of 1a are anticipated using medicinal chemistry techniques and molecular modeling to obtain analogs with higher affinity and better clinical therapeutic properties.