Cyclopamine

Last updated
Cyclopamine
Cyclopamine.svg
Cyclopamine-from-xtal-Mercury-3D-stick.png
Names
IUPAC name
17,23β-Epoxyveratraman-3β-ol
Systematic IUPAC name
(2′R,3S,3′R,3′aS,6′S,6aS,6bS,7′aR,11aS,11bR)-3′,6′,10,11b-Tetramethyl-1,2,3,3′a,4,4′,5′,6,6′,6a,6b,7,7′,7′a,8,11,11a,11b-octadecahydro-3′H-spiro[benzo[a]fluorene-9,2′-furo[3,2-b]pyridin]-3-ol
Other names
• 11-Deoxojervine
• (3β,23R)-17,23-Epoxyveratraman-3-ol
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.156.363 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C27H41NO2/c1-15-11-24-25(28-14-15)17(3)27(30-24)10-8-20-21-6-5-18-12-19(29)7-9-26(18,4)23(21)13-22(20)16(27)2/h5,15,17,19-21,23-25,28-29H,6-14H2,1-4H3/t15-,17+,19-,20-,21-,23-,24+,25-,26-,27-/m0/s1 Yes check.svgY
    Key: QASFUMOKHFSJGL-LAFRSMQTSA-N Yes check.svgY
  • InChI=1/C27H41NO2/c1-15-11-24-25(28-14-15)17(3)27(30-24)10-8-20-21-6-5-18-12-19(29)7-9-26(18,4)23(21)13-22(20)16(27)2/h5,15,17,19-21,23-25,28-29H,6-14H2,1-4H3/t15-,17+,19-,20-,21-,23-,24+,25-,26-,27-/m0/s1
    Key: QASFUMOKHFSJGL-LAFRSMQTBZ
  • C[C@H]1C[C@@H]2[C@H]([C@H]([C@]3(O2)CC[C@H]4[C@@H]5CC=C6C[C@H](CC[C@@]6([C@H]5CC4=C3C)C)O)C)NC1
Properties
C27H41NO2
Molar mass 411.630 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. 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. [1] 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. [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.

Contents

Discovery and naming

In 1957, Idaho sheep ranchers contacted the US Department of Agriculture (USDA) after 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. After a decade of trial and error, they came across wild corn lilies and advised the ranchers to avoid the corn lilies. 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]

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. Cyclopelamb2.jpg
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.

Source and structure

Cyclopamine consists of six rings, including a C-nor-D-homosteroid backbone linked to a octahydrofuro[3,2-b]pyridine system through a spirocentre. The molecule contains ten chiral centres, six of which at ring junctions.

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 [4] - conditions similar to those of gastric acid. [5] Veratramine is highly toxic, acting through excitation of the central nervous system causing seizures – similarly to serotonin. [6] 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. [6]

Proposed mechanism for the formation of veratramine from cyclopamine in acidic conditions. Mechanism of Cyclopamine Metabolism.jpg
Proposed mechanism for the formation of veratramine from cyclopamine in acidic conditions.

Mechanism

Cyclopamine impacts embryonic development by interrupting the sonic hedgehog (Shh) pathway.

In healthy development, the Shh gene codes for Shh proteins. These proteins have a high affinity for the surface membrane protein patched. Upon binding, Shh proteins inhibit patched. With the patch protein inhibited, another surface membrane protein smoothened 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. [2]

Embryological

Cyclopamine causes the most advanced form of holoprosencephaly. 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. [7]

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). Holoprosencephaly induced by Cyclopamine.jpg
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).

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. [3]

Medical potential

Cyclopamine is currently being investigated as a treatment agent in basal cell carcinoma, medulloblastoma and rhabdomyosarcoma (tumours commonly resulting from excessive Shh activity), [8] glioblastoma, and as a treatment agent for multiple myeloma. Studies of epithelial cancers have demonstrated that tumour cells secrete Shh ligand to signal adjacent growth factors production by stromal cells which leads to angiogenesis, tumour cell proliferation, and tumour cell survival. [3] [6]

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. [6] [3]

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. [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). 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. [9]

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. 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. Cyclopamine in Smoothened Receptor.png
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. 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.

See also

Related Research Articles

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

<span class="mw-page-title-main">Cyclopia</span> Congenital disorder

Cyclopia, also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities. Its incidence is 1 in 16,000 in born animals and 1 in 200 in miscarried fetuses.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Morphogen</span> Biological substance that guides development by non-uniform distribution

A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.

<span class="mw-page-title-main">GLI1</span> Protein-coding gene in humans

Zinc finger protein GLI1 also known as glioma-associated oncogene is a protein that in humans is encoded by the GLI1 gene. It was originally isolated from human glioblastoma cells.

<span class="mw-page-title-main">GLI2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.

<span class="mw-page-title-main">GLI3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.

The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.

<span class="mw-page-title-main">Smoothened</span> Gene found in humans and other animals

Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).

<span class="mw-page-title-main">Jervine</span> Chemical compound

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 by animals during a certain period of their gestation.

<i>Veratrum californicum</i> Species of plant

Veratrum californicum 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 as Durango; depending on latitude, it grows from near sea level to as high as 11,000 feet. It grows 1 to 2 meters tall, with an erect, unbranched, heavily leafy stem resembling a cornstalk. It prefers quite moist soil, and can cover large areas in dense stands near streams or in wet meadows. Many inch-wide flowers cluster along the often-branched top of the stout stem; they have 6 white tepals, a green center, 6 stamens, and a 3-branched pistil. The buds are tight green spheres. The heavily veined, bright green leaves can be more than a foot long.

mir-92 microRNA precursor family

The miR-92 microRNAs are short single stranded non-protein coding RNA fragments initially discovered incorporated into an RNP complex with a proposed role of processing RNA molecules and further RNP assembly. Mir-92 has been mapped to the human genome as part of a larger cluster at chromosome 13q31.3, where it is 22 nucleotides in length but exists in the genome as part of a longer precursor sequence. There is an exact replica of the mir-92 precursor on the X chromosome. MicroRNAs are endogenous triggers of the RNAi pathway which involves several ribonucleic proteins (RNPs) dedicated to repressing mRNA molecules via translation inhibition and/or induction of mRNA cleavage. miRNAs are themselves matured from their long RNA precursors by ribonucleic proteins as part of a 2 step biogenesis mechanism involving RNA polymerase 2.

<span class="mw-page-title-main">SUFU</span> Protein-coding gene in the species Homo sapiens

Suppressor of fused homolog is a protein that in humans is encoded by the SUFU gene. In molecular biology, the protein domain suppressor of fused protein (Sufu) has an important role in the cell. The Sufu is important in negatively regulating an important signalling pathway in the cell, the Hedgehog signalling pathway (HH). This particular pathway is crucial in embryonic development. There are several homologues of Sufu, found in a wide variety of organisms.

<span class="mw-page-title-main">GAS1</span> Protein-coding gene in the species Homo sapiens

Growth arrest-specific protein 1 is a protein that in humans is encoded by the GAS1 gene.

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 segmentation in the fly embryo, mutations in which may be embryonic lethal. Patched functions as the receptor for the Hedgehog protein and controls its spatial distribution, in part via endocytosis of bound Hedgehog protein, which is then targeted for lysosomal degradation.

<span class="mw-page-title-main">Vismodegib</span> Chemical compound

Vismodegib, sold under the brand name Erivedge, is a medication used 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 Administration (FDA) approval. The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011. The drug was developed by the biotechnology/pharmaceutical company Genentech.

<span class="mw-page-title-main">Saridegib</span> Experimental drug

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 as chondrosarcoma. IPI-926 exhibits its pharmacological effect by inhibition of the G protein-coupled receptor smoothened, a component of the hedgehog signaling pathway. Chemically, it is a semi-synthetic derivative of the alkaloid cyclopamine. The process begins with cyclopamine extracted from harvested Veratrum californicum which is taken through a series of alterations resulting in an analogue of the natural product cyclopamine, making IPI-926 the only compound in development/testing that is not fully synthetic.

<span class="mw-page-title-main">Hes3 signaling axis</span>

The STAT3-Ser/Hes3 signaling axis is a specific type of intracellular signaling pathway that regulates several fundamental properties of cells.

Hedgehog pathway inhibitors, also sometimes called hedgehog inhibitors, are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Due to the role of aberrant Hedgehog signaling in tumor progression and cancer stem cell maintenance across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy. Thus, Hedgehog pathway inhibitors are an important class of anti-cancer drugs. At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment. These include vismodegib and sonidegib, both inhibitors of Smoothened (SMO), which are being used for the treatment of basal cell carcinoma. Arsenic trioxide, an inhibitor of GLI transcription factors, is being used for the treatment of acute promyelocytic leukemia. In addition, multiple other Hedgehog pathway inhibitors are in different phases of clinical trials.

<span class="mw-page-title-main">Silmitasertib</span> Chemical compound

Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of protein kinase CK2, a constitutively active serine/threonine-specific protein kinase that is overexpressed in several types of tumors.

References

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  4. 1 2 Keeler, Richard F. (May 1969). "Toxic and teratogenic alkaloids of western range plants". Journal of Agricultural and Food Chemistry. 17 (3): 473–482. doi:10.1021/jf60163a012. ISSN   0021-8561.
  5. "The Role of HCL In Gastric Function And Health | Clinical Education". 2011-01-20. Retrieved 2023-10-14.
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  7. Hytham Nafady (2015-09-13). "Congenital brain malformations". Slideshare. Archived from the original on 2018-04-25. Retrieved 2018-05-09.
  8. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA (August 2000). "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine". Nature. 406 (6799): 1005–9. Bibcode:2000Natur.406.1005T. doi:10.1038/35023008. PMID   10984056. S2CID   4313790.
  9. 1 2 Dr. Sutherlin, Dan (2017). "Discovering Vismodegib in the Fight Against Skin Cancer: The First Approved Inhibitor of the Hedgehog Pathway" (PDF). American Chemical Society.

Further reading