Cyclopamine

Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily (Veratrum californicum) that causes fatal birth defects. It prevents the fetal brain from separating into two lobes (an extreme form of holoprosencephaly), which in turn causes the development of a single eye (cyclopia). The chemical was named after this effect, as it was originally noted by Idaho lamb farmers who contacted the US Department of Agriculture after their flocks gave birth to cycloptic lambs in 1957. It then took more than a decade to identify the corn lily as the culprit. Later work suggested that different rain patterns caused the sheep to graze differently, impacting the amount of corn lily ingested by pregnant sheep. The poison interrupts the sonic hedgehog signaling pathway during development, thus causing birth defects. Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs in the family of steroidal alkaloids. It is a teratogen isolated from the corn lily (Veratrum californicum) that causes fatal birth defects. It prevents the fetal brain from separating into two lobes (an extreme form of holoprosencephaly), which in turn causes the development of a single eye (cyclopia). The chemical was named after this effect, as it was originally noted by Idaho lamb farmers who contacted the US Department of Agriculture after their flocks gave birth to cycloptic lambs in 1957. It then took more than a decade to identify the corn lily as the culprit. Later work suggested that different rain patterns caused the sheep to graze differently, impacting the amount of corn lily ingested by pregnant sheep. The poison interrupts the sonic hedgehog signaling pathway during development, thus causing birth defects. In 1957 Idaho sheep ranchers contacted the US Department of Agriculture when their sheep gave birth to lambs with a fatal singular eye deformity. After collecting local flora and feeding it to mice, they struggled to recreate the cyclopia. After a decade of trial and error, they came across wild corn lilies and advised the ranchers to avoid the corn lilies. Cyclopamine was one of three steroidal alkaloids isolated from corn lily, but the only unknown at the time, and it was named after its effects on the fetal sheep. Four decades later a team lead by Professor Phillip Beachy related the sonic hedgehog gene to cyclopamine. Upon experimentation, they recreated cyclopia by silencing the sonic hedgehog gene. Professor Beachy then connected their cycloptic results to the cycloptic sheep noted four decades earlier. The biosynthesis of cyclopamine begins with cholesterol. A steroid skeleton has a classic 6-member ring, adjacent to another 6, 6, then a five or “6-6-6-5”. Veratum was determined to contain five types of alkaloids, each of which had a common cholesterol precursor: (1) solanidine alkaloids, (2) verazine alkaloids, (3) vertramine alkaloids, (4) jervine alkaloids, and (5) the cevanine alkaloids. In biosynthesis, Cyclopamine has a solanide (1) precursor, which itself is made from cholesterol. This was determined by initial studies which isolated alkaloids from corn lily (Veratrum californium), and introduced these to fetal sheep. At the time, jervine was an already known alkaloid which was isolated from corn lily alongside two other alkaloids: the unknown cyclopamine and veratramine; each with different toxicities. Later studies then demonstrated that jervine degraded to cyclopamine upon a Wolff-Kishner reduction, which helped identify the unknown compound. It was also demonstrated that treatment of cyclopamine with a Lewis acid (pH < 2) leads to the production of veratramine. The stomach provides these conditions, and thus only a small amount of cyclopamine passes through the stomach after ingestion. And even though only a small amount of ingested cyclopamine passes the stomach, it remains unaffected afterwards. Veratramine is highly toxic, even if it does not impact development, as it excites the central nervous system and can cause seizures- similarly to serotonin The mechanism for the production of veratramine focuses on the cleavage of a carbon-oxygen bond, which leads to the formation of a new double bond. From there, this ring is almost aromatic. The driving force to become aromatic then pushes an elimination reaction, creating a third double bond and producing aromaticity, as depicted in figure below.