Cyclopean sheep give cancer hope

Back in 1957, shepherds in the mountainous US state of Idaho discovered that when pregnant sheep ate lilies of the species Veratrum californicum (California corn lily or Californian false hellebore) they tended to give birth to lambs with a single eye in the centre of the forehead, a condition known, for obvious reasons, as cyclopia.

Researchers found that the condition was triggered by a steroidal alkaloid to which they not unpredictably gave the name “cyclopamine”.

Over 50 years later, cyclopamine is being investigated as a candidate for cancer therapy. It is the first inhibitor of a signalling pathway that is used by cells to react to external signals. The pathway is known as the hedgehog signal-transduction pathway, after a signal protein that carries out an important function in embryonic development and has been given the name “hedgehog” for reasons I will not go into here.

Malfunction of the pathway leads to massive deformations (such as cyclopia) during embryonic development. But it can also cause cancer in adults, and so inhibiting the pathway is therefore a possible cancer treatment.

Why is this research taking place only now? Until recently, there has been no efficient way to synthesise cyclopamine, since its unusual structure has many peculiarities that make manufacture difficult. But a joint German and Greek research team from the universities of Leipzig, in Germany, and Thessaloniki, in Greece, has overcome the difficulties to develop a 20-step synthesis starting from dehydroepiandrosterone, a commercially available natural steroid hormone. The strategy has achieved an overall yield of 1 per cent, which is considered good for such a difficult synthesis.

In addition, the researchers have found that by slightly modifying the reagents they can produce cyclopamine analogues that do not occur in nature. They hope to use these compounds to examine further the biological activity of cyclopamine and attain a broader understanding of its structure-activity relationships. This work could lead to the development of analogues with tuned bioactivity for use as new anticancer agents.