Forced degradation studies of rapamycin: Identification of autoxidation products

Alan R Oyler, Brigitte E. Segmuller, Yanqiu Sun, Ann Polshyna, Richard Dunphy, Barbara L. Armstrong, Patrick Achord, Cynthia A. Maryanoff, Lori Alquier, Yuri V. Il'ichev

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 10. S-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.

Original languageEnglish (US)
Pages (from-to)194-200
Number of pages7
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume59
Issue number1
DOIs
StatePublished - Feb 5 2012

Bibliographical note

Funding Information:
One of the authors (Alan R. Oyler) has a financial interest consisting of ownership of stock and stock options in Johnson & Johnson. In addition, the studies conducted at the University of Minnesota Duluth were supported by a grant from Cordis Corporation . The authors thank Mr. Paul A. Mickelson for technical assistance.

Keywords

  • Autoxidation
  • Epoxides
  • Isomerization
  • NP-HPLC
  • Sirolimus

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