Cyclopamine

Basic Info

Common NameCyclopamine(F05224)
2D Structure
Description

Cyclopamine 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.

FRCD IDF05224
CAS Number4449-51-8
PubChem CID442972
FormulaC27H41NO2
IUPAC Name

(3S,3'R,3'aS,6'S,6aS,6bS,7'aR,9R,11aS,11bR)-3',6',10,11b-tetramethylspiro[2,3,4,6,6a,6b,7,8,11,11a-decahydro-1H-benzo[a]fluorene-9,2'-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-ol

InChI Key

QASFUMOKHFSJGL-LAFRSMQTSA-N

InChI

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

Canonical SMILES

CC1CC2C(C(C3(O2)CCC4C5CC=C6CC(CCC6(C5CC4=C3C)C)O)C)NC1

Isomeric SMILES

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

Synonyms
        
            11-Deoxojervine
        
            Jervine, 11-deoxo-
        
            CYCLOPAMINE
        
            4449-51-8
        
            UNII-ZH658AJ192
        
            CHEBI:4021
        
            CHEMBL254129
        
            11-Deoxyjervine
        
            ZH658AJ192
        
            HSDB 3505
Classifies
                

                  
                    Plant Toxin
Update DateNov 13, 2018 17:07

Chemical Taxonomy

KingdomOrganic compounds
SuperclassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
SubclassSteroidal alkaloids
Intermediate Tree NodesNot available
Direct ParentJerveratrum-type alkaloids
Alternative Parents
Molecular FrameworkAliphatic heteropolycyclic compounds
SubstituentsJerveratrum-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
DescriptionThis compound 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.

Properties

Property NameProperty Value
Molecular Weight411.63
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count3
Rotatable Bond Count0
Complexity801
Monoisotopic Mass411.314
Exact Mass411.314
XLogP3.5
Formal Charge0
Heavy Atom Count30
Defined Atom Stereocenter Count10
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Isotope Atom Count0
Covalently-Bonded Unit Count1

ADMET

Model Result Probability
Absorption
Blood-Brain BarrierBBB+0.9670
Human Intestinal AbsorptionHIA+1.0000
Caco-2 PermeabilityCaco2+0.5450
P-glycoprotein SubstrateSubstrate0.7655
P-glycoprotein InhibitorNon-inhibitor0.6076
Non-inhibitor0.7318
Renal Organic Cation TransporterNon-inhibitor0.6939
Distribution
Subcellular localizationLysosome0.4682
Metabolism
CYP450 2C9 SubstrateNon-substrate0.8655
CYP450 2D6 SubstrateNon-substrate0.6854
CYP450 3A4 SubstrateSubstrate0.6615
CYP450 1A2 InhibitorNon-inhibitor0.9036
CYP450 2C9 InhibitorNon-inhibitor0.9100
CYP450 2D6 InhibitorNon-inhibitor0.8896
CYP450 2C19 InhibitorNon-inhibitor0.8951
CYP450 3A4 InhibitorNon-inhibitor0.9547
CYP Inhibitory PromiscuityLow CYP Inhibitory Promiscuity0.8905
Excretion
Toxicity
Human Ether-a-go-go-Related Gene InhibitionWeak inhibitor0.7330
Non-inhibitor0.8635
AMES ToxicityNon AMES toxic0.8029
CarcinogensNon-carcinogens0.9637
Fish ToxicityHigh FHMT0.6796
Tetrahymena Pyriformis ToxicityHigh TPT0.9136
Honey Bee ToxicityHigh HBT0.6600
BiodegradationNot ready biodegradable0.9921
Acute Oral ToxicityIII0.6697
Carcinogenicity (Three-class)Non-required0.4810
Model Value Unit
Absorption
Aqueous solubility-4.1047LogS
Caco-2 Permeability1.1127LogPapp, cm/s
Distribution
Metabolism
Excretion
Toxicity
Rat Acute Toxicity2.2544LD50, mol/kg
Fish Toxicity1.3453pLC50, mg/L
Tetrahymena Pyriformis Toxicity0.3746pIGC50, ug/L

References

TitleJournalDatePubmed ID
Targeting the cancer initiating cell: the Achilles' heel of cancer.Adv Enzyme Regul201121035484
Comparison of the teratogenicity in rats of certain potato-type alkaloids and the veratrum teratogen cyclopamine.Lancet1973 May 264123576

Targets

Target Details

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
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 ]
Target Details

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
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 ]