Identification and Structure Elucidation of Cyclopamine Degradation

The steroidal alkaloids of Veratrum californicum (V. californicum) have been studied extensively due to their bioactivity. Most of these alkaloids are teratogens, i.e. a compound that increases the incidence of abnormal prenatal development. One such steroidal alkaloid, cyclopamine, has been found to be an antagonist of the hedgehog signaling pathway and is currently gaining widespread use in the development of novel cancer chemotherapeutics and probing mechanisms of action in developmental biology. A closely related teratogenic alkaloid, veratramine, shows no ability to down regulate the hedgehog pathway and has long been thought to result from the acid degradation of cyclopamine; a deterrent to using cyclopamine as an orally administered cancer treatment. Recent studies have shown the natural degradation pathway for cyclopamine, first proposed in the 1960’s, may be incorrect, and the alternative end product to cyclopamine degradation may be very difficult to differentiate from either cyclopamine or veratramine. Our current effort is to isolate and characterize the cyclopamine degradation product using high performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy