Abstract |
The effect of acid treatment of cyclopamine, a natural antagonist of the hedgehog (Hh) signaling pathway and a potential anti- cancer drug, has been studied. Previous reports have shown that under acidic conditions, as in the stomach, cyclopamine is less effective. Also, it has been stated that cyclopamine converts to veratramine, which has side effects such as hemolysis. In this study, we examined in detail the influence of acidification on structure and activity of cyclopamine. We found that of acidified cyclopamine converts to two previously unreported isomers, which we have called cyclopamine (S) and cyclopamine (X). These have likely gone undetected because cyclopamine is often analyzed with fast and hence lower resolving chromatographic methods. Compared to natural cyclopamine, these cyclopamine isomers have a significantly reduced effect on the ciliary transport of the Hh receptor smoothened, and reduced inhibition on the Hedgehog signaling pathway. The side effects of these isomers are unknown. Our findings can partly explain a reduced efficiency of cyclopamine in a gastric environment, and may help with the rational design of more pH independent cyclopamine analogues.
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Authors | Steven Ray Wilson, Martin Frank Strand, Andreas Krapp, Frode Rise, Dirk Petersen, Stefan Krauss |
Journal | Journal of pharmaceutical and biomedical analysis
(J Pharm Biomed Anal)
Vol. 52
Issue 5
Pg. 707-13
(Sep 05 2010)
ISSN: 1873-264X [Electronic] England |
PMID | 20236786
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | 2010 Elsevier B.V. All rights reserved. |
Chemical References |
- Hedgehog Proteins
- Veratrum Alkaloids
- cyclopamine
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Topics |
- Animals
- Chromatography, Liquid
- Fluorescent Antibody Technique
- Hedgehog Proteins
(antagonists & inhibitors)
- Isomerism
- Magnetic Resonance Spectroscopy
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Quantum Theory
- Spectrometry, Mass, Electrospray Ionization
- Veratrum Alkaloids
(chemistry, pharmacology)
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