HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Hedgehog antagonist cyclopamine isomerizes to less potent forms when acidified.

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.
AuthorsSteven Ray Wilson, Martin Frank Strand, Andreas Krapp, Frode Rise, Dirk Petersen, Stefan Krauss
JournalJournal of pharmaceutical and biomedical analysis (J Pharm Biomed Anal) Vol. 52 Issue 5 Pg. 707-13 (Sep 05 2010) ISSN: 1873-264X [Electronic] England
PMID20236786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2010 Elsevier B.V. All rights reserved.
Chemical References
  • Hedgehog Proteins
  • Veratrum Alkaloids
  • cyclopamine
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: