Cyclopamine (T3D4082)

IdentificationTaxonomyBiological PropertiesPhysical PropertiesToxicity ProfileSpectraConcentrationsLinksReferencesGene RegulationTargets (2)XML
Targets (2)
Record Information
Version2.0
Creation Date2014-08-29 05:04:23 UTC
Update Date2014-12-24 20:26:38 UTC
Accession NumberT3D4082
Identification
Common NameCyclopamine
ClassSmall Molecule
DescriptionCyclopamine is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloids. It is a teratogen isolated from the corn lily (Veratrum californicum) that causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes (holoprosencephaly) and cause the development of a single eye (cyclopia). It does so by inhibiting the hedgehog signaling pathway (Hh). Cyclopamine is useful in studying the role of Hh in normal development, and as a potential treatment for certain cancers in which Hh is overexpressed.
Compound Type
  • Amine
  • Ether
  • Natural Compound
  • Organic Compound
  • Plant Toxin
Chemical Structure
Thumb
MOLSDFPDBSMILESInChI
Synonyms
Synonym
11-Deoxyjervine
[3H]-Cyclopamine.11-Deoxojervine
Chemical FormulaC27H41NO2
Average Molecular Mass411.620 g/mol
Monoisotopic Mass411.314 g/mol
CAS Registry Number4449-51-8
IUPAC Name(1'S,2R,2'R,3R,3aS,5'S,6S,7aR,10'S,11'S)-2',3,6,15'-tetramethyl-3a,4,5,6,7,7a-hexahydro-3H-spiro[furo[3,2-b]pyridine-2,14'-tetracyclo[8.7.0.0²,⁷.0¹¹,¹⁶]heptadecane]-7',15'-dien-5'-ol
Traditional Namecyclopamine
SMILES[H][C@@]12C[C@]([H])(C)CN[C@@]1([H])[C@@]([H])(C)[C@@]1(CC[C@]3([H])C(C[C@@]4([H])[C@@]3([H])CC=C3C[C@@]([H])(O)CC[C@]43C)=C1C)O2
InChI IdentifierInChI=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
InChI KeyInChIKey=QASFUMOKHFSJGL-LAFRSMQTSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as jerveratrum-type alkaloids. These are steroidal alkaloids with a structure that is based on the jervane ring system. Jerveratrum alkaloids have alkamines with 1-3 oxygen atoms, and occur as such or as monoglycosides.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassSteroidal alkaloids
Direct ParentJerveratrum-type alkaloids
Alternative Parents
Substituents
  • Jerveratrum-type alkaloid
  • Azasteroid
  • Alkaloid or derivatives
  • Piperidine
  • Cyclic alcohol
  • Tetrahydrofuran
  • Secondary alcohol
  • Oxacycle
  • Dialkyl ether
  • Secondary aliphatic amine
  • Ether
  • Azacycle
  • Secondary amine
  • Organoheterocyclic compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Alcohol
  • Hydrocarbon derivative
  • Organopnictogen compound
  • Amine
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Actin Cytoskeleton
  • Actin Filament
  • Axoneme
  • Cell junction
  • Cell surface
  • Centrosome
  • Clathrin Coated Vesicle
  • Cytosol
  • Endoplasmic reticulum
  • Extracellular
  • Extracellular matrix
  • Focal adhesion
  • Membrane
  • Microtubule
  • Mitochondrial Membrane
  • Mitochondrion
  • Peroxisome
  • Plasma Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
ApoptosisNot Availablemap04210
Hedgehog Signaling PathwayNot AvailableNot Available
Cell cycleNot Availablemap04110
Notch signaling pathwayNot Availablemap04330
Insulin secretionNot Availablemap04911
Axon guidanceNot Availablemap04360
Rna polymeraseNot Availablemap03020
Nucleotide Excision RepairSMP00478 map03420
Mapk signaling pathwayNot Availablemap04010
EndocytosisNot Availablemap04144
Dna replicationNot Availablemap03030
Base excision repairNot Availablemap03410
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0038 g/LALOGPS
logP4.27ALOGPS
logP3.8ChemAxon
logS-5ALOGPS
pKa (Strongest Acidic)18.2ChemAxon
pKa (Strongest Basic)10.03ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area41.49 ŲChemAxon
Rotatable Bond Count0ChemAxon
Refractivity122.17 m³·mol⁻¹ChemAxon
Polarizability50.91 ųChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-01ox-1119600000-bba2ea28c0ff0f8502522016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00dl-4579200000-4e2e431075c7e58843262016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9010000000-a6d4623d57d584b45a292016-08-02View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-0112900000-a167919b081486158c7d2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03di-0107900000-8cf159fa6dfd830b0d212016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0fxy-9314000000-271f222e1c894052d5592016-08-03View Spectrum
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityCyclopamine causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes (holoprosencephaly) and cause the development of a single eye (cyclopia). It does so by inhibiting the hedgehog pathway (Hh). Cyclopamine inhibits the Hh by influencing the balance between the active and inactive forms of the smoothened protein. Cyclopamine is useful in studying the role of Hh in normal development, and as a potential treatment for certain cancers in which Hh is overexpressed. Cyclopamine acts as a primary inhibitor of the hedgehog signaling pathway in cells. This pathway named for the ligand for the signal protein, is used by cells to help them react to external chemical signals. The pathway carries out important functions in embryonic development and when it goes awry, deformities can occur. However, errant activation of the pathway can also trigger cancer in adult humans, leading to basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and prostate, pancreatic and breast cancers. A way of controlling the pathway using cyclopamine could turn this problem on its head and provide a way to treat cancer. (Wikipedia) Cyclopamine inhibits the Hh pathway by binding to and preventing the activation of Smoothened (Smo), preventing downstream target gene regulation. (1)
MetabolismNot Available
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesIt is a teratogen isolated from the corn lily (Veratrum californicum) that causes usually fatal birth defects. Cyclopamine is useful in studying the role of Hh in normal development, and as a potential treatment for certain cancers in which Hh is overexpressed.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDNot Available
PubChem Compound ID442972
ChEMBL IDCHEMBL254129
ChemSpider ID391275
KEGG IDC10798
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDST3D4082.pdf
General References
  1. Lipinski RJ, Hutson PR, Hannam PW, Nydza RJ, Washington IM, Moore RW, Girdaukas GG, Peterson RE, Bushman W: Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol Sci. 2008 Jul;104(1):189-97. doi: 10.1093/toxsci/kfn076. Epub 2008 Apr 14. [18411234 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

Target Details
1. Smoothened homolog
General Function:
Wnt-protein binding
Specific Function:
G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7 and GLI3 in the cilia.
Gene Name:
SMO
Uniprot ID:
Q99835
Molecular Weight:
86395.95 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
Inhibitory0.0127 uMNot AvailableBindingDB 50232973
IC500.064 uMNot AvailableBindingDB 50232973
IC500.28 uMNot AvailableBindingDB 50232973
IC500.3 uMNot AvailableBindingDB 50232973
Dissociation0.0124 uMNot AvailableBindingDB 50232973
References
  1. Wang J, Mook RA Jr, Lu J, Gooden DM, Ribeiro A, Guo A, Barak LS, Lyerly HK, Chen W: Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling. Bioorg Med Chem. 2012 Nov 15;20(22):6751-7. doi: 10.1016/j.bmc.2012.09.030. Epub 2012 Sep 23. [23063522 ]
  2. Solinas A, Faure H, Roudaut H, Traiffort E, Schoenfelder A, Mann A, Manetti F, Taddei M, Ruat M: Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity. J Med Chem. 2012 Feb 23;55(4):1559-71. doi: 10.1021/jm2013369. Epub 2012 Feb 10. [22268551 ]
  3. Peukert S, Jain RK, Geisser A, Sun Y, Zhang R, Bourret A, Carlson A, Dasilva J, Ramamurthy A, Kelleher JF: Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway. Bioorg Med Chem Lett. 2009 Jan 15;19(2):328-31. doi: 10.1016/j.bmcl.2008.11.096. Epub 2008 Dec 3. [19091559 ]
Target Details
2. Sonic hedgehog protein
General Function:
Zinc ion binding
Specific Function:
Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction. Activates the transcription of target genes by interacting with its receptor PTCH1 to prevent normal inhibition by PTCH1 on the constitutive signaling activity of SMO (By similarity).
Gene Name:
SHH
Uniprot ID:
Q15465
Molecular Weight:
49606.685 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.6 uMNot AvailableBindingDB 50232973
References
  1. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]