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

doi:10.1016/j.jpba.2011.10.017

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

Chemistry & Biochemistry

Research output: Contribution to journal › Article › peer-review

12 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 language	English (US)
Pages (from-to)	194-200
Number of pages	7
Journal	Journal of Pharmaceutical and Biomedical Analysis
Volume	59
Issue number	1
DOIs	https://doi.org/10.1016/j.jpba.2011.10.017
State	Published - 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.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

Autoxidation
Epoxides
Isomerization
NP-HPLC
Sirolimus

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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.",

keywords = "Autoxidation, Epoxides, Isomerization, NP-HPLC, Sirolimus",

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

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. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1016/j.jpba.2011.10.017",

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AU - Segmuller, Brigitte E.

AU - Sun, Yanqiu

AU - Polshyna, Ann

AU - Dunphy, Richard

AU - Armstrong, Barbara L.

AU - Achord, Patrick

AU - Maryanoff, Cynthia A.

AU - Alquier, Lori

AU - Il'ichev, Yuri V.

N1 - 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. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2012/2/5

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N2 - 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.

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KW - Autoxidation

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KW - Isomerization

KW - NP-HPLC

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Forced degradation studies of rapamycin: Identification of autoxidation products

Abstract

Bibliographical note

Keywords

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