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Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. It is a 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. The molecule was named after this effect, which was originally observed by Idaho lamb farmers in 1957 after their herds gave birth to cycloptic lambs. It then took more than a decade to identify corn lily as the culprit. 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. Cyclopamine interrupts the sonic hedgehog signalling pathway, instrumental in early development, ultimately causing birth defects.
The Veratrum species were found to contain five related families of alkaloid: (1) solanidine alkaloids, (2) verazine alkaloids, (3) veratramine alkaloids, (4) jervine alkaloids, and (5) the cevanine alkaloids, each of which with cholesterol as a common precursor.
In its proposed biosynthesis, cyclopamine has a solanidine precursor. This was determined through initial studies which isolated alkaloids from Veratrum californium, and introduced these to embryonic sheep.
Considering its formation in vivo, the treatment of cyclopamine with dilute hydrochloric acid (0.5%) at 38 °C leads to the formation of veratramine - conditions similar to those of gastric acid. Veratramine is highly toxic, acting through excitation of the central nervous system causing seizures – similarly to serotonin. The mechanism for the formation of veratramine from cyclopamine is proposed to take place through the cleavage of the spirocyclic carbon-oxygen bond in the THF ring, which through elimination leads to the formation of a double bond. Afforded by the strong driving force afforded by aromatisation, ultimately a benzene ring forms.
Later studies also demonstrated that jervine could be degraded to cyclopamine through a Wolff-Kishner reduction, which served as evidence for the structure of cyclopamine. from cyclopamine in acidic conditions. ]]
In healthy development, the Shh gene codes for the Shh protein. This protein has a high affinity for the cell receptor patched. Upon binding, SHH forms an inhibitory complex with patched. With the patch protein inhibited, another surface membrane protein known as smoothened may signal further cascades which impact development.
Cyclopamine has a high affinity for smoothened – and upon binding, inhibits the signal. Even though Shh still binds Patched, Smoothened cannot signal in the presence of cyclopamine and thus the pathway is interrupted.
With this in mind, one can imagine cyclopamine as a way of attenuating cancer's mechanism. However, while cyclopamine has been demonstrated to inhibit tumor growth in mouse xenograft models, it never reached therapeutic potential as it caused many side effects including weight loss, dehydration, and death in mouse models.
Two functional analogs of cyclopamine have been approved by the FDA; vismodegib in 2012, and sonidegib in 2015. Vismodegib was the first Shh pathway drug approved for treating cancer.
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). The hydrogen bonds form at two sites: as a donor at a tyrosine residue and as an acceptor at an arginine residue. Whilst the hydrogen bond accepting group is more impactful, having both makes for stronger binding.
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