|
NMR spectroscopy has been used in structural studies and a novel synthesis of a compound, cyclopamine, which is found in corn lilies and causes lambs born of ewes that eat the lilies to be born with a single eye in the middle of their foreheads. The compound might one day redeem itself as a human anticancer drug. In 1957, shepherds in Idaho, USA, started to report that their ewes were giving birth to cyclops-like lambs with under-developed brains and other birth defects. A US Department of Agriculture study was initiated to identify the cause. After living down on the sheep farm for three years, staff member Lynn James discovered that the local wild corn lilies were to blame. Those ewes munching on the lilies, Veratrum californicum (also known as the California false hellebore) gave birth to the cyclops lambs. However, it wasn't for another eight years of painstaking research that the chemical trigger for the mutations was pinned down to an alkaloid in the corn lilies, which was dubbed unsurprisingly, cyclopamine. Medicinal chemists are, of course, always on the look out for novel structures with unusual physiological activity, especially if it involves developmental or genetic damage. Such seemingly negative activity can often be put to good use in drugs for adults by using it to damage and kill cancer cells. Investigations of cyclopamine, also known as 11-deoxojervine, revealed it to be one such compound and it has since proven itself to be an effective candidate for cancer therapy in adult humans with clinical trials now underway. Studies suggest that cyclopamine acts as a primary inhibitor of the so-called "hedgehog" signal-transduction pathway in cells. This pathway named for the ligand for the signal protein, is used by cells to help them react to external chemical signals. The pathway carries out important functions in embryonic development and when it goes awry, as happens when cyclopamine from corn lilies blocks the pathway, deformities can occur, such as the cyclopia seen in the Idaho lambs. However, errant activation of the pathway can also trigger cancer in adult humans, leading to basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and prostate, pancreatic and breast cancers. A way of controlling the pathway using cyclopamine could turn this problem on its head and provide a way to treat cancer, many anticancer drugs are paradoxically carcinogenic in healthy individuals. Meanwhile, Athanassios Giannis, Philipp Heretsch, and Anne Stoessel of the University of Leipzig, Germany and Vasiliki Sarli of the University of Thessaloniki, Greece, have developed a chemical synthesis for the compound. Writing in the journal Angewandte Chemie, Giannis and his team suggest that their synthesis will help researchers broaden our understanding of the structure-activity relationships of cyclopamine even further. Moreover, synthesis could be adapted to allow analogues of this unusual structure to be produced that might be fine-tuned for specific biological activity. Giannis and colleagues are the first chemists to devise a synthesis for cyclopamine, which is not surprising given the peculiar structure of this unusual steroidal alkaloid. They have circumvented several difficulties in reconstructing the compound from simple starting materials in a relatively efficient twenty-one step synthetic process based on commercially available dehydroepiandrosterone, which is a natural steroid hormone. The team explains that their synthesis employs transformations that mimic various biochemical reactions and transformations that replicate the three-dimensional structure, or stereochemistry, of the compound. However, a twenty-one step synthesis is rather long-winded for any pharmaceutical manufacturing process. This is especially so given that the overall yield from start to finish is a mere 1%. The team asserts that this is, nevertheless, a good result for such a tricky synthesis, and will be improved as they improve efficiency at each step. Importantly, the synthesis allows the team to produce analogues of cyclopamine, variations on the theme, that are not known to occur in nature, which could be investigated to reveal which aspects of the whole compound are essential for its biological activity. It could turn out that a much simpler analogue has improved activity and is easier to make in higher yield as well as being a more potent anticancer agent than the natural product. "Studies and biological evaluations are currently being conducted and will be reported in due course," the team concludes.
Related links: The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
|
 Cyclopamine causes cyclopia in lambs but has anticancer effects |
