Structure of FK506, a novel immunosuppressant isolated from Streptomyces

Tanaka, Hirokazu; Kuroda, Akio; Marusawa, Hiroshi; Hatanaka, Hiroshi; Kino, Toru; Goto, Toshio; Hashimoto, Masashi; Taga, Toru

doi:10.1021/ja00250a050

Cited by 521 publications

(203 citation statements)

References 4 publications

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“…1 The restricted rotation of the amide bond leads to the existence in solution of two conformational isomers (rotamers); the ratio of these rotamers is solvent-dependent and they are detectable by low-column temperature HPLC 2 and 1 H NMR. 3 In addition, the presence of three adjacent carbonyl groups is responsible for the formation of two tautomeric structures, identified after isolation and purification in 1993: 2 one lacking the hemiketal ring, compound 2 (tautomeric compound I), and the other having opposite stereochemistry at C-10, compound 3 (tautomeric compound II). (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Evaluation, synthesis and characterization of tacrolimus impurities

et al. 2012

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Tacrolimus is an immunosuppressant macrolactam of fermentative origin. By means of HPLC, LC-MS and NMR analyses, coupled with the reference standard synthesis, the main impurities of tacrolimus bulk drug samples were identified and their chemical-physical properties reported. Known ascomycin and tautomers I and II were detected. The correct relative retention time HPLC value of 39,40-dihydro tacrolimus was established. The not described 23,24-anhydro derivative was detected and completely characterized. A full characterization of ascomycin and 39,40-dihydro tacrolimus was also reported.

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Section: Introductionmentioning

confidence: 99%

Evaluation, synthesis and characterization of tacrolimus impurities

et al. 2012

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“…4 This compound, which is a sphingosine (2) analogue, modulates the immune system by a unique mechanism, i.e., disruption of normal lymphocyte trafficking. Specifically, 1 inhibits egress of lymphocytes from secondary lymphoid tissues, such as lymph nodes; 5 the biomarker of 1 is thus lymphopenia (abnormally low numbers of circulating lymphocytes).…”

Section: Introductionmentioning

confidence: 99%

“…6 In vivo phosphorylation of 1 by Sphk2 a produces the S-phosphate species 1-P specifically, 7 which mimics much of S1P's (2-P in Chart 1 is an important extracellular lipid mediator) biological behavior. Compound 2-P signals cells via five GPCRs: S1P [1][2][3][4][5] (formerly, EDG1, EDG5, EDG3, EDG6, and EDG8). 8 Compound 1-P is an agonist at four of the five receptors: S1P 1 , S1P 3 , S1P 4 , and S1P 5 .…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Zhu

Snyder²,

Kharel³

et al. 2007

J. Med. Chem.

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Compound 1 (FTY720, Fingolimod) represents a new generation of immunosuppressant that modulates lymphocyte trafficking by interacting with the S1P 1 receptor. Compound 1 also provides a template molecule for studying the molecular biology of S1P receptors and related enzymes (kinases and phosphatases). In this study, two conformationally constrained analogues of 1 (3a and 3c) were asymmetrically synthesized in high optical purity. In vitro assessment documented that both analogues are Sphk2 substrates, their phosphorylated species are potent S1P 1 receptor agonists, and 3a-P is a potent S1P 3 antagonist. After oral administration in mice, both compounds evoked lymphopenia, but their duration of action differed markedly.

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“…Tacrolimus (FK506) is a macrolide compound isolated from Streptomyces tsukubaensis, a soil fungus found in Northern Japan [14]. Since its discovery in 1984, tacrolimus has been increasingly used in transplantation.…”

Section: Introductionmentioning

confidence: 99%

Increased tacrolimus levels during diarrhea

Hochleitner¹,

Bösmüller²,

Nehoda³

et al. 2001

Transplant International

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While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

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Structure of FK506, a novel immunosuppressant isolated from Streptomyces

Cited by 521 publications

References 4 publications

Evaluation, synthesis and characterization of tacrolimus impurities

Evaluation, synthesis and characterization of tacrolimus impurities

Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Increased tacrolimus levels during diarrhea

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