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Hedgehog antagonist cyclopamine isomerizes to less potent forms when acidified
Steven Ray Wilson1, Martin Frank Strand, Andreas Krapp
1Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, NO-0315, Oslo, Norway. stevenw@kjemi.uio.no
Journal of Pharmaceutical and Biomedical Analysis
|March 19, 2010
Summary
Acid treatment of cyclopamine, a potential anti-cancer drug, forms two new isomers (S and X). These isomers show reduced activity in the hedgehog signaling pathway, explaining decreased effectiveness in acidic environments.
Area of Science:
- Pharmacology
- Organic Chemistry
- Molecular Biology
Background:
- Cyclopamine is a natural antagonist of the hedgehog (Hh) signaling pathway.
- Cyclopamine is a potential anti-cancer drug but shows reduced efficacy in acidic conditions.
- Acidic conditions may convert cyclopamine to veratramine, causing side effects like hemolysis.
Purpose of the Study:
- To investigate the structural and activity changes of cyclopamine under acidic conditions.
- To identify new cyclopamine derivatives formed during acidification.
- To understand the reduced effectiveness of cyclopamine in acidic environments.
Main Methods:
- Acidification of cyclopamine.
- Analysis of cyclopamine structure and activity using high-resolution chromatography.
- Assessment of the effect of cyclopamine isomers on Hh receptor smoothened transport.
Main Results:
- Acidification of cyclopamine yields two novel isomers: cyclopamine (S) and cyclopamine (X).
- These isomers exhibit significantly reduced inhibition of the Hedgehog signaling pathway compared to natural cyclopamine.
- The reduced activity of these isomers may explain cyclopamine's lower efficacy in acidic environments.
Conclusions:
- Acidification of cyclopamine leads to the formation of less active isomers.
- These findings provide insights into cyclopamine's behavior in the gastric environment.
- The study aids in designing future cyclopamine analogs with improved pH stability for cancer therapy.
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