title: Forced degradation studies of rapamycin: identification of autoxidation products.
abstract: The immunosuppressant drug rapamycin, also known as Sirolimus, underwent autoxidation under mild conditions to give numerous monomeric and oligomeric compounds, which were generally characterized by size-exclusion chromatography and NP-HPLC with UV and MS detection. Some of the more predominant products, epoxides and ketones, were isolated and identified. Two epoxides and 10S-epimer of rapamycin were described for the first time. Observed rapamycin isomers were also addressed. Computational chemistry was used to provide mechanistic insights. Formation of the majority of the rapamycin products could be rationalized with free radical-mediated autoxidation reactions involving alkene and alcohol sites. Methodological aspects of oxidative stress testing are discussed.
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, USA. aoyler@d.umn.edu
authors.forename: Alan R
authors.initials: AR
authors.lastname: Oyler
authors.forename: Brigitte E
authors.initials: BE
authors.lastname: Segmuller
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Sun
authors.forename: Ann
authors.initials: A
authors.lastname: Polshyna
authors.forename: Richard
authors.initials: R
authors.lastname: Dunphy
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Armstrong
authors.forename: Patrick
authors.initials: P
authors.lastname: Achord
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Maryanoff
authors.forename: Lori
authors.initials: L
authors.lastname: Alquier
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Il'ichev
mesh_terms: D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D019281:Dimerization; D004355:Drug Stability; D004852:Epoxy Compounds / Q000302:isolation & purification*; D007166:Immunosuppressive Agents / Q000032:analysis* / Q000737:chemistry; D007536:Isomerism; D007659:Ketones / Q000302:isolation & purification*; D013058:Mass Spectrometry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D020123:Sirolimus / Q000032:analysis* / Q000737:chemistry
chemical_list: D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D007659:Ketones; D020123:Sirolimus