Cyclopamine

It is a teratogenic component of corn lily (Veratrum californicum), which when consumed during gestation has been demonstrated to induce birth defects, including the development of a single eye (cyclopia) in offspring.

[2] Later work suggested that differing rain patterns had changed grazing behaviours, which led to a greater quantity of corn lily to be ingested by pregnant sheep.

[3] Cyclopamine interrupts the sonic hedgehog signalling pathway, instrumental in early development, ultimately causing birth defects.

Cyclopamine was discovered as one of three steroidal alkaloids isolated from Veratrum californicum and was named after its effects on sheep embryos.

Four decades later, a team led by Professor Phillip Beachy linked the effect of cyclopamine to the sonic hedgehog gene.

Cyclopia was induced through silencing the sonic hedgehog gene, suggesting Cyclopamine acted through a similar mechanism.

[2] Cyclopamine consists of six rings, including a C-nor-D-homosteroid backbone linked to a octahydrofuro[3,2-b]pyridine system through a spirocentre.

[5] Veratramine is highly toxic, acting through excitation of the central nervous system causing seizures – similarly to serotonin.

[9] Vismodegib was designed to account for hydrogen bonding with the Smoothened receptor and to overcome the solubility issues of cyclopamine (through inclusion of the chlorine atom).

Head of a lamb born by a sheep that consumed Veratrum californicum (California corn lily). Cyclopia is induced by the cyclopamine and other teratogenic alkaloids present in the plant.
Proposed mechanism for the formation of veratramine from cyclopamine in acidic conditions. [ 4 ]
In this figure, the healthy brain (left) has two lobes whereas the developmentally affected brain through action of cyclopamine (right) has a severe state of holoprosencephaly and is alobar (has no lobes).
The structural similarities and differences between cyclopamine and vismodegib (a drug derived from cyclopamine). Both interrupt sonic hedgehog signalling; however vismodegib is more soluble and is a FDA approved drug. The 3D structure is a representation of the binding of cyclopamine in the Smoothened receptor, which would have been discovered through crystallisation and X-ray crystallography. [ 3 ] There are two main hydrogen bonds which stabilise this interaction: one in which a tyrosine residue acts as a hydrogen bond donor, and one in which an arginine acts as a hydrogen bond acceptor. A main difference between vismodegib and cyclopamine is that the pyridine nitrogen of vismodegib is a more effective proton acceptor than the THF ring oxygen in cyclopamine. Because of this, vismodegib has a higher affinity for the receptor.