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
''Veratrum californicum'' (California corn lily, white or California false hellebore) is an extremely poisonous plant native to western North America, including the Sierra Nevada and Rocky Mountains, as far north as Washington and as far south ...
'') that causes fatal birth defects. It prevents the embryonic brain from separating into two lobes (an extreme form of
holoprosencephaly
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed an ...
), which in turn causes the development of a single eye (
cyclopia
Cyclopia (named after the Greek mythology character cyclopes) is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of ...
). 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 herds 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
Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''.
This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...
signaling pathway during development, thus causing birth defects.
Discovery and naming
In 1957, Idaho sheep ranchers contacted the US Department of Agriculture (USDA) when their sheep gave birth to lambs with a fatal singular eye deformity. After collecting local flora and feeding them to mice, USDA scientists struggled to recreate the
cyclopia
Cyclopia (named after the Greek mythology character cyclopes) is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of ...
. 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 ''
Veratrum californicum
''Veratrum californicum'' (California corn lily, white or California false hellebore) is an extremely poisonous plant native to western North America, including the Sierra Nevada and Rocky Mountains, as far north as Washington and as far south ...
'', known also as the California corn lily, but the only unknown at the time, and it was named after its effects on sheep embryos. Four decades later a team led 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.
Source and structure
The biosynthesis of cyclopamine begins with
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
. A steroid skeleton has a classic 6-member ring, adjacent to another 6, 6, then a five or "6-6-6-5". ''Veratrum'' was determined to contain five types of alkaloids, each of which had a common cholesterol precursor: (1)
solanidine
Solanidine is a poisonous steroidal alkaloid chemical compound that occurs in plants of the family Solanaceae, such as potato and '' Solanum americanum''. Human ingestion of solanidine also occurs via the consumption of the glycoalkaloids, α-so ...
alkaloids, (2) verazine alkaloids, (3)
vertramine alkaloids, (4)
jervine
Jervine is a steroidal alkaloid with molecular formula C27H39NO3 which is derived from the plant genus ''Veratrum''. Similar to cyclopamine, which also occurs in the genus ''Veratrum'', it is a teratogen implicated in birth defects when consumed ...
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 embryonic 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
Veratramine is an alkaloid
Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some sy ...
. 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
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
.
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
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
. The driving force to become aromatic then pushes an elimination reaction, creating a third double bond and producing
aromaticity
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to saturate ...
, as depicted in the figure below.
Mechanism
Cyclopamine impacts embryonic development by hindering the sonic hedgehog (Shh) pathway.
In healthy development, the Shh gene codes for Shh proteins. These proteins have a high affinity for a surface membrane protein called "
Patched
Patched (Ptc) is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. Patched is an essential gene in embryogenesis for proper segme ...
". Upon binding, Shh proteins inhibit Patched. With Patch inhibited, another surface membrane protein called "
Smoothened
Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecula ...
" may signal further cascades which impact development.
Cyclopamine has a high affinity for Smoothened – and upon binding, inhibits the signal. Even though Shh may inhibit Patched, Smoothened cannot signal in the presence of Cyclopamine and thus the pathway is interrupted.
Embryological
Cyclopamine causes the most advanced form of
holoprosencephaly
Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation. Normally, the forebrain is formed an ...
. Because it blocks Shh signaling, the embryonic brain no longer divides into lobes (becomes alobar). Thus, only one optical track develops, hence the cycloptic (singular) eye. Furthermore, this disease is fatal and presently has no cure.
![Holoprosencephaly induced by Cyclopamine](https://upload.wikimedia.org/wikipedia/commons/a/a3/Holoprosencephaly_induced_by_Cyclopamine.jpg)
One can imagine one half of the healthy brain not dividing, but instead growing out and resembling the alobar brain. This occurs in cases of cyclopamine poisoning. This malformation is always fatal, and it is worth noting that there are lesser cases of holoprosencephaly that are not always fatal. However, embryonic cyclopamine poisoning causes the most extreme and therefore fatal cases.
Medical potential
Cyclopamine is currently being investigated as a treatment agent in
basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
,
medulloblastoma
Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa.
The brain is divided into two ...
, and
rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the tumor are identified as rhabdomyoblasts.
There are four subt ...
, tumors that commonly result from excessive SHh activity,
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...
, and as a treatment agent for
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
. For example, studies of epithelial cancers have demonstrated that tumor cells secrete Shh ligand to signal adjacent growth factors production by
stromal cell
Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa ...
s which leads to
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, tumor cell proliferation, and tumor cell survival.
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.
Having said that, two
functional analogs of cyclopamine have been approved by the FDA;
vismodegib
Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
in 2012, and
sonidegib
Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.
Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism).
Approvals and indications
It was approved for medical use in the United State ...
in 2015. Furthermore, vismodegib was the first Shh pathway drug approved for treating cancer.
While cyclopamine and vismodegib do not appear very similar, the development of vismodegib revealed which aspects of cyclopamine give it functionality and used those results to make vismodegib. For example, the added chlorine group in Vismodegib gives the drug a much higher solubility than cyclopamine – low solubility is a hindrance towards making cyclopamine a practical drug. The development of vismodegib revealed structure activity relationships (SAR), and determined that hydrogen bonding in two sites, as well as solubility, impact the effectiveness of the drug. Specifically speaking, the two hydrogen bonds work in opposite ways; at one site a tyrosine residue on the Smoothened receptor offers a proton to be accepted whereas a separate arginine residue works as a hydrogen bond acceptor. While the accepting group is more impactful, having both makes for stronger binding.
See also
*
Saridegib
Saridegib, also known as IPI-926, is an experimental drug candidate undergoing clinical trials for the treatment of various types of cancer, including hard-to-treat hematologic malignancies such as myelofibrosis and ligand-dependent tumors such ...
(also known as IPI-926), a
semisynthetic
Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
analog of cyclopamine
*
Vismodegib
Vismodegib (trade name Erivedge ) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administrati ...
, an artificial Hh signaling inhibitor
*
Sonidegib
Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.
Sonidegib is Hedgehog signaling pathway inhibitor (via smoothened antagonism).
Approvals and indications
It was approved for medical use in the United State ...
, an artificial Hh signaling inhibitor
*
Steroidal alkaloid
Steroidal alkaloids have organic ring backbones which feature nitrogen-based functional groups. More specifically, they are distinguished by their tetracyclic cyclopentanophenanthrene backbone that marks their close relationship with sterols. They ...
, the family of molecules cyclopamine falls in
References
Further reading
*
Cancer Drug Behind Cyclops Birth? ''Wired News''
*
**
*
*
*
*
{{refend
Jervines
Teratogens
Spiro compounds
Secondary alcohols
Nitrogen heterocycles
Oxygen heterocycles
Plant toxins