Journal
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
Volume 52, Issue 5, Pages 707-713Publisher
ELSEVIER
DOI: 10.1016/j.jpba.2010.02.017
Keywords
Cyclopamine; Hedgehog; Isomerization; NMR; LC-MS
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The effect of acid treatment of cyclopamine, a natural antagonist of the hedgehog (HI,) signaling pathway and a potential anti-cancer drug, has been studied Previous reports have shown that uncle acidic conditions, as in the stomach. cyclopamine is less effective Also, it has been stated that cyclopamine converts to vetatramine, 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 'some's. which we have called cyclopamine (S) and cyclopamine (X) These have likely gone undetected because cyclopamine is often analyzed with fast and hence lower solving chromatographic methods Compared to natural cyclopamine, these cyclopamine isomers have a significantly reduced effect on the ciliary transport of the His 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 (C) 2010 Elsevier B V All rights reserved
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