Total synthesis of FK506 and an FKBP probe reagent, [C(8),C(9)-13C2]-FK506

Nakatsuka, Masashi; Ragan, John A.; Sammakia, Tarek; Smith, David B.; Uehling, David; Schreiber, Stuart L.

doi:10.1021/ja00170a024

Cited by 253 publications

(77 citation statements)

References 4 publications

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“…Several NMR studies for structure determination and synthesis of tacrolimus were performed by several groups, e.g., Nakatsuka et al (16) and Mierke et al (17) in the early 1990s. In these studies, tacrolimus was dissolved in deuterated chloroform and methanol due to the limited aqueous solubility of tacrolimus.…”

Section: Discussionmentioning

confidence: 99%

Reutilization of Tacrolimus Extracted from Expired Prograf® Capsules: Physical, Chemical, and Pharmacological Assessment

et al. 2015

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Abstract. In this study, we investigated whether tacrolimus extracted and purified from the commercial capsules (Prograf® 5 mg) have retained its original quality and activity beyond the capsules expiration date in order to be reused for research purposes after extraction. High-performance liquid chromatography (HPLC) assay method was developed and validated for the quantification of tacrolimus, using cyclosporine A as an internal standard (IS). Moreover, a combination of analytical methods, including nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), Fourier transform-infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and differential scanning calorimetry (DSC) were used to assess the quality of extracted/purified tacrolimus. Suppression of murine peripheralblood mononuclear cells (PBMC) proliferation and the levels of interleukin-2 (IL-2) and interferon gamma (IFN-γ) were also assessed. The data obtained showed no detectable differences in the quality profile between the authentic sample and extracted drug. Also, the results showed that the extracted/ purified tacrolimus was able to suppress T cell proliferation, induced by concanavalin A, indicating the retained pharmacological activity. We proved that tacrolimus extracted/purified from expired Prograf® capsuled retains its purity and immunosuppressive activity and can be reused for research and possibly in pharmaceutical manufacturing.

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Section: Discussionmentioning

confidence: 99%

Reutilization of Tacrolimus Extracted from Expired Prograf® Capsules: Physical, Chemical, and Pharmacological Assessment

et al. 2015

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“…Application of 1.3-dithiane and dimethyl acetal protecting groups in the synthesis of the immunosuppressant FK506 by S . L. Schreiber et al [41].…”

Section: Introduction Of "Stand-ins"mentioning

confidence: 99%

Protecting Group Strategies in Organic Synthesis

Schelhaas

Waldmann

1996

Angew. Chem. Int. Ed. Engl.

317

168

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The choice of protecting groups is one of the decisive factors in the successful realization of a complex, demanding synthetic project. The protecting groups used influence the length and efficiency of the synthesis and are often responsible for its success or failure. A wide range of blocking groups are currently available for the different functional groups; however, an overall strategy combining these different masking techniques in an advantageous and reliable ' manner has never been proposed or at best only for individual cases. This review attempts to make a contribution to filling this gap. First a very short overview of the most commonly used protecting groups will be given, in which they are classified according to their lability and not according to the functional group they protect. This classification clarifies coherent concepts for the development of blocking strategies. On the basis of this brief summary reliable strategies will then be illustrated and developed with selected examples from the recent literature by which protecting groups may be combined successfully and advantageously in synthetic projects of differing degrees of complexity and difficulty.

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“…These labelled products were needed to clarify the mode of avermectin biological action thought to be the selective blockade of gamma-aminobutyric acid mediated neurotransmission. In a related report and motivated by the need to achieve higher specific activity, Toth and co-workers prepared [22, H] ivermectin by the homogeneous catalytic tritiation of avermectin B 1 a. 4 Most likely the steric bulk of the Wilkinson's catalyst facilitated the selective reduction of one olefin in the presence of four others and the compound was prepared at a specific activity of 57.7 Ci/mmol, allowing its nematotoxic activity to be studied.…”

Section: Highly Functionalized Macrocyclesmentioning

confidence: 99%

“…21 For an entirely different reason the Schreiber group at Harvard synthesized [8,9-13 C] tacrolimus. 22 The lengthy asymmetric synthesis was designed to provide a product needed to clarify the interaction between tacrolimus and its receptor, the immunophilin FKBP. Lilly chemists appear to be the first to have published the labelling of erythromycin with 14 C. 23 The antibiotic was first demethylated and the resulting precursor was converted to [Nmethyl- 14 formaldehyde.…”

Section: Highly Functionalized Macrocyclesmentioning

confidence: 99%