4449-51-8 Usage
Description
Cyclopamine is a natural steroidal alkaloid that inhibits signaling through the hedgehog pathway at the level of the pathway activator Smoothened. By altering gene expression in this signaling sequence, cyclopamine induces defects in morphogenesis, first observed in chicks and sheep as cyclopia. As a readout of action, cyclopamine inhibits hedgehog-dependent expression of Pax7 with an IC50 value of 24 nM. Although teratogenic during development, cyclopamine has potential applications in the treatment of cancer. It is a white crystalline solid.
Uses
1. Used in Pharmaceutical Industry:
Cyclopamine is used as a hedgehog [Hh] signaling pathway and Smo inhibitor for its potential applications in the treatment of cancer. It depletes stem-like cancer cells in glioblastoma and blocks tumor engraftment.
2. Used in Cancer Research:
Cyclopamine is used as a tool in cancer research to study the effects of oncogenic mutations in Smoothened and Patched, as it has been shown to reverse these effects.
3. Used in Stem Cell Differentiation:
Cyclopamine is used to induce differentiation of human embryonic stem cells (hESCs) into hormone-expressing endocrine cells.
4. Used in Antimicrobial Applications:
Cyclopamine is used for its antibacterial properties, providing a potential application in the development of new antimicrobial agents.
5. Used in Teratogenic Studies:
Cyclopamine demonstrates teratogenic properties and has been used in studies to understand the effects of teratogens on developmental processes.
Cyclopamine
cyclopamine is a ?isosteroidal alkaloid isolated from Veratrum plant , it mainly exists in four kinds of liliaceous plants which include North America Veratrum californicum , Indian Cornlily and Veratrum grandiflorum , Fritillaria pallidiflora Schrenk ,it can be combined with the Smoothened (Smo) protein in Hedgehog signaling pathway , thereby inhibiting the protein activity. It was discovered in the 1960s because of its teratogenic effects , but later nineties studies show that cyclopamine is a hedgehog signaling pathway inhibitor, it has been demonstrated in Drosophila body, since the hedgehog signaling pathway mutations are associated with the pathogenesis of a variety of tumors , recent studies have found that cyclopamine have anti-tumor effects in the adult, which has been confirmed in experiments in vivo or in vitro about pancreatic cancer, bile duct cancer, ovarian cancer, liver cancer and others , but on its researches about gastric cancer cells,it has not been reported in the country . Currently cyclopamine as a potential anti-cancer drug in the world sets off a wave of research.
The above information is edited by the lookchem of Tian Ye.
Biological Activity
Inhibitor of hedgehog (Hh) signaling, likely via direct inhibition of Smoothened, the accessory protein to the putative Hh receptor Patched. Anti-cancer and teratogenic in vivo . Depletes stem-like cancer cells in glioblastoma and blocks tumor engraftment.
Anticancer Research
Cyclopamine is a natural compound that inhibits the Hedgehog signaling pathway.Cyclopamine targets Hedgehog by specifically hindering SMO activation.Cyclopamine therapy of murine medulloblastoma resulted in the inhibition ofproliferation, induction of neuronal differentiation, effective depletion of CSCs, andreduction of tumor burden in a mouse tumor allograft. Cyclopamine is effective inkilling of pancreatic, breast, and multiple myeloma CSCs. Cyclopamine incombination with gemcitabine inhibits metastatic spread and reduces primary tumorburden in pancreatic orthotopic xenografts. Mammosphere formation in breastcarcinoma and SC proliferation in multiple myeloma can be reduced by cyclopamine(Kawasaki et al. 2008). The HH ligand activation requires cholesterol at theircarboxyl ends, and 22-OH-cholesterol and 20-OH-cholesterol are reported toincrease the HH target gene expression, and this hypothesis of cholesterol-dependentHH signal transduction is investigated in M2-10B4 pluripotent mesenchymal stemcells. The mechanism underlying the positive regulation of HH signaling by theseoxidative species of cholesterol is not clear. However, this oxidative status ofcholesterol is altered by the endogenous ROS. Hence, the bioactive food componentsthat control the ROS levels can be important in regulating self-renewal and HHpathways (Kim et al. 2012). Cholecalciferol (vitamin D3, an isoform of vitamin D)is reported to be HH antagonist in vitro but not in vivo. Binding of cholecalciferol toSMO receptors results in the reduction of HH signaling in MDAMB231 andC3H/10 T1/2 fibroblast cells. 1 μM vitamin D3 shows more potent SMO inhibitoryaction than 10 μM cyclopamine in PTCH1-transfected C3H/10 T1/2 cells (Kimet al. 2012). Curcumin interferes with the Gli1 mRNA or Gli reporter activity andinhibits HH signaling in transgenic mouse prostate adenocarcinoma cells (Kimet al. 2012).
References
1) Watkins et al. (2003), Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer; Nature, 422 313
Check Digit Verification of cas no
The CAS Registry Mumber 4449-51-8 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 4,4,4 and 9 respectively; the second part has 2 digits, 5 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 4449-51:
(6*4)+(5*4)+(4*4)+(3*9)+(2*5)+(1*1)=98
98 % 10 = 8
So 4449-51-8 is a valid CAS Registry Number.
InChI: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
4449-51-8Relevant articles and documents
The Transformation of Jervine into 18-Functional C-Nor-D-homosteroids
Suginome, Hiroshi,Yonekura, Norihisa,Masamune, Tadashi
, p. 210 - 213 (1980)
N,O-Diacetyldeoxojervine, obtained by the Wolff-Kishner reduction of jervine followed by acetylation, has been catalytically hydrogenated to (22S,25S)-N,3-O-diacetyl-5α-veratranine-3β,23β-diol.Irradiation in benzene containing mercury(II) oxide and iodine afforded 20-formyl-17β-ethyl-12α-etiojervan-3β-ol 3-acetate which was converted into 17β-ethyl-3β-hydroxy-12α-etiojervan-20-one 3-acetate by dye-sensitized photo-oxygenation of the corresponding morpholine enamine.Reduction to 17β-ethyl-12α-etiojervane-3β,20β-diol 3-acetate with sodium borohydride followed by irradiation in benzene in the presence of mercury(II) oxide and iodine afforded an 18-functional C-nor-D-homosteroid, (20R)-18,20-epoxy-17β-ethyl-12α-etiojervane-3β,20β-diol.The configuration of the methyl group on the tetrahydrofuran ring has been shown to be α on the basis of the NMR spectrum, confirming a previous assignment.
11-Deoxojervine, a new alkaloid from Veratrum species.
Masamune,Mori,Takasugi,Murai,Ohuchi,Sato,Katsui
, p. 1374 - 1378 (1965)
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A new cyclopamine glucuronide prodrug with improved kinetics of drug release
Renoux, Brigitte,Legigan, Thibaut,Bensalma, Souheyla,Chadeneau, Corinne,Muller, Jean-Marc,Papot, Sebastien
experimental part, p. 8459 - 8465 (2012/04/23)
We prepared a new glucuronide prodrug of cyclopamine designed to target selectively the Hedgehog signalling pathway of cancer cells. This prodrug includes a novel self-immolative linker bearing a hydrophilic side chain that can be easily introduced via "click chemistry". With this design, the prodrug exhibits reduced toxicity compared to the free drug on U87 glioblastoma cells. However, in the presence of β-glucuronidase, the prodrug conducts to the quick release of cyclopamine thereby restoring its antiproliferative activity. The Royal Society of Chemistry 2011.
Synthesis of cyclopamine using a biomimetic and diastereoselective approach
Giannis, Athanassios,Heretsch, Philipp,Sarli, Vasiliki,Stoessel, Anne
supporting information; experimental part, p. 7911 - 7914 (2010/03/30)
From Homer to hedgehog: Cyclopamine, the first inhibitor of the hedgehog signaling pathway, causes cyclopia in embryos butin adults it is a potent anticancer drug. A concise biomimetic and diastereoselective synthesis of cyclopamine (2) starting from comm
