Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives.

Fujita, Tetsuro; Inoue, Ken‐ichiro; Yamamoto, Satoshi; Ikumoto, Takeshi; Sasaki, S.; Toyama, R.; Chiba, Kenji; Hoshino, Yukio; Okumoto, Takeki

doi:10.7164/antibiotics.47.216

Cited by 74 publications

(43 citation statements)

References 8 publications

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“…Chemical modification of ISP-1 led to a novel synthetic immunosuppressant, FTY720, which has more potent immunosuppressive activity and less toxicity than ISP-1 (Fujita et al, 1994b). FTY720 administered at 0.1 mg/kg or more significantly prolonged the survival of skin, cardiac, liver, renal, pancreas, lung, and small bowel allografts in rats (Brinkmann et al, 2001).…”

mentioning

confidence: 99%

Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment

Fujino

Funeshima²,

Kitazawa³

et al. 2003

J Pharmacol Exp Ther

263

180

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Experimental autoimmune encephalomyelitis (EAE) is a T-celldependent autoimmune disease that reproduces the inflammatory demyelinating pathology of multiple sclerosis (MS). We investigated the efficacy and mechanism of immunosuppression against EAE by administering 2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride (FTY720) in Lewis rats immunized with myelin basic protein together with complete Freund's adjuvant. FTY720 treatment almost completely protected the rats against disease. The protection by FTY720 was associated with a dramatic reduction in the number of lymphocytes staining for T-cell receptors in the spinal cord as examined by immunohistochemistry. The mRNA expression of Th1 cytokines interleukin (IL)-2, IL-6, and interferon-␥ in the spinal cord was also reduced dramatically as assessed by reversetranscription polymerase chain reaction. Furthermore, lymphocytes isolated from the spleen of FTY720-treated rats were transferred into naive recipient rats against EAE manifestation by reducing both disease incidence and clinical score. These results suggested that the protective anti-inflammatory effect of treatment with FTY720 was, to a large extent, due to the inhibition of encephalitogenic T-cell responses and/or their migration into the central nervous system and may be a potential candidate for use in treating patients with MS.

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mentioning

confidence: 99%

Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment

Fujino

Funeshima²,

Kitazawa³

et al. 2003

J Pharmacol Exp Ther

263

180

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“…Previous studies on the structure-activity relationship of myriocin, a sphingoid base isolated from Isaria sinclairii (the imperfect stage of Cordyceps sinclairii ), have shown that 2-substituted 2-aminoethanol is the minimum essential structure for the immunosuppressive activity of myriocin29. Selective acetylation or complete acetylation of the amino group greatly decreased the immunosuppressive activity of myriocin3031. More recently, it was revealed that sphingoid base analogs are substrates of sphingosine kinase (SPHKs) due to their structural homology to sphingosine.…”

Section: Discussionmentioning

confidence: 99%

New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

Han

et al. 2016

Sci Rep

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A comprehensive identification of sphingoid bases and ceramides in wild Cordyceps was performed by integrating a sequential chromatographic enrichment procedure and an UHPLC-ultrahigh definition-Q-TOF-MS based sphingolipidomic approach. A total of 43 sphingoid bases and 303 ceramides were identified from wild Cordyceps, including 12 new sphingoid base analogues and 159 new ceramide analogues based on high-resolution MS and MS/MS data, isotope distribution, matching with the comprehensive personal sphingolipid database, confirmation by sphingolipid standards and chromatographic retention time rule. The immunosuppressive bioassay results demonstrated that Cordyceps sphingoid base fraction exhibits more potent immunosuppressive activity than ceramide fraction, elucidating the immunosuppressive ingredients of wild Cordyceps. This study represented the most comprehensive identification of sphingoid bases and ceramides from a natural source. The findings of this study provided an insight into therapeutic application of wild Cordyceps.

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“…(7, 21, 22) The SAR studies on these ISP-I homologues, including semi-synthetic derivatives, revealed that neither the functionalities (the 14-ketone, the 6-double bond, and the 4-hydroxy group) nor the configuration at the carbon bearing the 3-hydroxy group are so important for its activity; however, critical problems such as toxicity and insolubility remained to be solved. Therefore, simplification of the structure of ISP-I was conducted to reduce its toxicity and to improve its physicochemical properties (Fig.…”

Section: A Fortuitous Discovery Of Fty720mentioning

confidence: 99%

FTY720 Story. Its Discovery and the following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology

Adachi

Chiba

2007

Perspect Medicin Chem

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Fingolimod (FTY720) is the first of a novel class: sphingosine 1-phosphate (S1P) receptor modulator and is currently in phase 3 clinical trials for multiple sclerosis (MS). FTY720 was first synthesized in 1992 by chemical modification of an immunosuppressive natural product, ISP-I (myriocin). ISP-I was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp that was an ‘eternal youth’ nostrum in traditional Chinese medicine. ISP-I is an amino acid having three successive asymmetric centers and some functionalities. We simplified the structure drastically to find a nonchiral symmetric 2-substitued-2-aminopropane-1,3-diol framework for an in vivo immunosuppressive activity (inhibition of rat skin allograft rejection test or prolonging effect on rat skin allograft survival) and finally discovered FTY720. During the course of the lead optimization process, we encountered an unexpected dramatic change of the mechanism of action with an in vivo output unchanged. Since it proved that FTY720 did not inhibit serine palmitoyltransferase that is the target enzyme of ISP-I, reverse pharmacological approaches have been preformed to elucidate that FTY720 is mainly phosphorylated by sphingosine kinease 2 in vivo and the phosphorylated drug acts as a potent agonist of four of the five G protein coupled receptors for S1P: S1P1, S1P3, S1P4 and S1P5. Evidence has accumulated that immunomodulation by FTY720-P is based on agonism at the S1P1 receptor. Medicinal chemistry targeting S1P1 receptor agonists is currently in progress. The FTY720 story provides a methodology where in vivo screens rather than in vitro screens play important roles in the lead optimization. Unlike recent drug discovery methodologies, such a strategy as adopted by the FTY720 program would more likely meet serendipity.

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Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives.

Cited by 74 publications

References 8 publications

Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment

Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment

New Immunosuppressive Sphingoid Base and Ceramide Analogues in Wild Cordyceps

FTY720 Story. Its Discovery and the following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology

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