Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720

Kiuchi, Masatoshi; Adachi, Keishi; Kohara, Toshiyuki; Teshima, Koji; Masubuchi, Yumi; Mishina, Tadashi; Fujita, Tetsuro

doi:10.1016/s0960-894x(97)10188-3

Cited by 57 publications

(44 citation statements)

References 11 publications

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“…To demonstrate that local agonist production can lead to PE, we compared the effects of two synthetic sphingosine stereoisomers (20) of 2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (21,22), of which only the R but not the S isomer is a sphingosine kinase substrate. Only the R enantiomer induced PE (Fig.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

Gon

Wood²,

Kiosses³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

123

118

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Pulmonary pathologies including adult respiratory distress syndrome are characterized by disruption of pulmonary integrity and edema compromising respiratory function. Sphingosine 1-phosphate (S1P) is a lipid mediator synthesized and/or stored in mast cells, platelets, and epithelial cells, with production up-regulated by the proinflammatory cytokines IL-1 and TNF. S1P administration via the airways but not via the vasculature induces lung leakage. Using receptor-null mice, we show that S1P, acting on S1P3 receptor expressed on both type I and type II alveolar epithelial cells but not vascular endothelium, induces pulmonary edema by acute tight junction opening. WT but not S1P3-null mice showed disruption of pulmonary epithelial tight junctions and the appearance of paracellular gaps between epithelial cells by electron microscopy within 1 h of airways exposure to S1P. We further show by fluorescence microscopy that S1P induced rapid loss of ZO-1 reactivity, an essential component of the cytoplasmic plaque associated with tight junctions, as well as of the tetraspannin Claudin-18, an integral membrane organizer of tight junctions. S1P shows synergistic activity with the proinflammatory cytokine TNF, showing both pulmonary edema and mortality at subthreshold S1P doses. Specifically, preexposure of mice to subthreshold doses of TNF, which alone induced no lung edema, exacerbated S1P-induced edema and impaired survival. S1P, acting through S1P3, regulates epithelial integrity and acts additively with TNF in compromising respiratory barrier function. Because S1P3-null mice are resistant to S1P-induced pulmonary leakage, either alone or in the presence of TNF, S1P3 antagonism may be useful in protecting epithelial integrity in pulmonary disease

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Section: Resultsmentioning

confidence: 99%

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

Gon

Wood²,

Kiosses³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

123

118

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“…4d). In contrast, no significant differences were found in the CD4 ϩ / CD25 ϩ T cell subset, despite the fact that a further reduction of mRNA for S1P 1 and S1P 4 receptors were found in these cells after FTY720 treatment. Thus, these data indicate that CD4 ϩ /CD25 ϩ T cells are less responsive to S1P and that this altered response may explain the differences seen in sequestration of this T cell subset after FTY720 treatment in vivo.…”

Section: Cd4mentioning

confidence: 63%

“…T he novel immunomodulator FTY720, a chemical derivative of myriocin, shares structural similarities with sphingosine 1-phosphate (S1P), 2 a natural lysophospholipid known to regulate a wide variety of fundamental functions including cell survival, cytoskeletal rearrangements, and cell motility (1,2). FTY720 becomes phosphorylated by sphingosine kinases and the phosphorylated form (FTY-P) acts as an agonist on four of the five known S1P receptors, S1P 1 , S1P 3 , S1P 4 , and S1P 5 (3,4).…”

mentioning

confidence: 99%

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

Sawicka

Dubois

Járai

et al. 2005

The Journal of Immunology

130

105

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The sphingosine 1-phosphate (S1P) receptor agonist FTY720 is well known for its immunomodulatory activity, sequestering lymphocytes from blood and spleen into secondary lymphoid organs and thereby preventing their migration to sites of inflammation. Because inflammation is critically dependent on a balance between Ag-specific Th/effector cells and T-regulatory cells, we investigated the effect of FTY720 on T-regulatory cell trafficking and functional activity. An increased number of CD4+/CD25+ T cells was found in blood and spleens of FTY720-treated mice, and transfer of these cells resulted in a significantly more pronounced accumulation in spleens but not lymph nodes after treatment, suggesting that this compound differentially affects the homing properties of T-regulatory cells compared with other T cell subsets. Indeed, CD4+/CD25+ T cells express lower levels of S1P1 and S1P4 receptors and demonstrate a reduced chemotactic response to S1P. Moreover, analysis of the functional response of FTY720-treated CD4+/CD25+ T cells revealed an increased suppressive activity in an in vitro Ag-specific proliferation assay. This correlated with enhanced function in vivo, with T-regulatory cells obtained from FTY720-treated mice being able to suppress OVA-induced airway inflammation. Thus, FTY720 differentially affects the sequestration of T-regulatory cells and importantly, increases the functional activity of T-regulatory cells, suggesting that it may have disease-modifying potential in inflammatory disorders.

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“…In fact, providing synthetic sphingolipids might have better outcomes for therapeutic purposes since availability and rapid metabolism of natural sphingolipids limit their utilization. FTY720 is a chemically synthesizable analog for sphingosine [143] which was shown to be effective for the treatment of CLL and CML [144,145]. Mechanism of action is dependent on protein phosphatase 2A (PP2A) activation resulting in shutting down of the signaling pathways driving leukomogenesis [146][147][148].…”

Section: Sphingolipids In the Perspective Of Chemo-therapeutic Responsementioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720

Cited by 57 publications

References 11 publications

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

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Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720

Cited by 57 publications

References 11 publications

RETRACTED: S1P 3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

RETRACTED: S1P 3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

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Product

Resources

About

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

RETRACTED: S1P ₃ receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF