title: Some transformations of tacrolimus, an immunosuppressive drug.
abstract: Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the β-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-Δ(5,6)-tacrolimus and 5-deoxy-Δ(5,6)-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8-epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-Δ(5,6)-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ(5,6)-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the β-hydroxyketone moiety. ¹H and ¹³C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.
authors.affiliation: Department of Drug Design and Pharmacology, School of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Dorthe M
authors.initials: DM
authors.lastname: Skytte
authors.affiliation: Department of Drug Design and Pharmacology, School of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Jaroszewski
authors.affiliation: Department of Drug Design and Pharmacology, School of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Johansen
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Steen Honoré
authors.initials: SH
authors.lastname: Hansen
authors.affiliation: Veloxis Pharmaceuticals A/S, Kogle Allé 4, DK-2970 Hørsholm, Denmark.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Veloxis Pharmaceuticals A/S, Kogle Allé 4, DK-2970 Hørsholm, Denmark.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, School of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: karla.frydenvang@sund.ku.dk.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
mesh_terms: D001557:Benzenesulfonates / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D000440:Butanols / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D004355:Drug Stability; D005609:Free Radicals / Q000737:chemistry; D006358:Hot Temperature / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000032:analysis / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D066244:Proton Magnetic Resonance Spectroscopy; D012015:Reference Standards; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D001557:Benzenesulfonates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000440:Butanols; D005609:Free Radicals; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; C077664:tert-butoxide, potassium; C013554:1,5-diazabicyclo(4.3.0)non-5-ene; C029501:4-toluenesulfonic acid; D016559:Tacrolimus