Natural Product (NP) Details

General Information of the NP (ID: NP5775)
Name
Cyclopamine
Synonyms
CYCLOPAMINE; 11-Deoxojervine; 4449-51-8; 11-Deoxyjervine; UNII-ZH658AJ192; CHEBI:4021; CHEMBL254129; ZH658AJ192; (2'R,3S,3'R,3a'S,6aS,6bS,6'S,7a'R,11aS,11bR)-3',6',10,11b-tetramethyl-1,2,3,3a',4,4',5',6,6a,6b,6',7,7',7a',8,11,11a,11b-octadecahydro-3'H-spiro[benzo[a]fluorene-9,2'-furo[3,2-b]pyridin]-3-ol; Spiro[9H-benzo[a]fluorene-9,2'(3'H)-furo[3,2-b]pyridin]-3-ol, 1,2,3,3'a,4,4',5',6,6',6a,6b,7,7',7'a,8,11,11a,11b-octadecahydro-3',6',10,11b-tetramethyl-, (2'R,3S,3'R,3'aS,6'S,6aS,6bS,7'aR,11aS,11bR)- (9CI); (3beta,22S,23R)-17,23-epoxyveratraman-3-ol; HSDB 3505; CY8; [3H]-Cyclopamine; Jervine, 11-deoxo-; DSSTox_CID_23709; DSSTox_RID_80067; DSSTox_GSID_43709; SCHEMBL29153; BSPBio_001032; MLS006010945; Veratraman-3-ol, 17,23-epoxy-, (3beta,23beta)-; Jervine, 11-deoxo- (7CI); DTXSID6043709; GTPL10328; AOB1606; EX-A952; BCPP000271; HMS1792D13; HMS1990D13; HMS3403D13; ZINC4098868; Tox21_300632; BDBM50232973; MFCD01735266; NSC734950; s1146; AKOS024456709; BCP9000568; CCG-208181; CS-0633; NSC 734950; NSC-734950; NCGC00163474-03; NCGC00163474-04; NCGC00163474-07; NCGC00254431-01; HY-17024; SMR001822854; CAS-4449-51-8; (3beta23R)-17,23-Epoxyveratraman-3-ol; AB0007896; 6832-EP2316832A1; 6832-EP2316833A1; C10798; W-5421; SR-05000002357; Veratraman-3-ol,23-epoxy-, (3-beta,23-beta)-; Q-200904; Q3271319; SR-05000002357-2; BRD-K58938839-001-03-8; (3alpha,8alpha,14beta,22S,23R)-17,23-epoxyveratraman-3-ol; Veratraman-3-ol, 17,23-epoxy-, (3-beta,23-beta)- (9CI); (2'R,3S,3'R,3'aS,6'S,6aS,6bS,7'aR,11aS,11bR)-1,2,3,3'a,4,4',5',6,6',6a,6b,7,7',7'a,8,11,11a,11b-Octadecahydro-3',6',10,11b-tetramethylspiro[9H-benzo[a]fluorene-9,2'(3'H)-furo[3,2-b]pyridin]-3-ol; 11051-96-0; Spiro(9H-benzo(a)fluorene-9,2-b)pyridin)-3-o l, 1,2,3,3'a,4,4',5',6,6',6a,6b,7,7',7'a,8,11,11a,11b-octa deca hydro-3',6',10,11b-tetramethyl-, (2'R,3S,3'R,3'aS,6'S,6aS,6bS,7'aR,11aS,11bR)-
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Species Origin Veratrum californicum ...     Click to Show/Hide
Veratrum californicum
Kingdom: Viridiplantae
Phylum: Streptophyta
Class: Magnoliopsida
Order: Liliales
Family: Melanthiaceae
Genus: Veratrum
Species: Veratrum californicum
Disease Prostate hyperplasia [ICD-11: GA90] Investigative [1]
Structure
Click to Download Mol
2D MOL

3D MOL

ADMET Property
Absporption
Caco-2 Permeability
 -4.978
 
MDCK Permeability
 -4.954
 
PAMPA
 -
 
HIA
 - - -
 
Distribution
VDss
 0.034
 
PPB
 64.5%
 
BBB
 - -
 
Metabolism
CYP1A2 inhibitor
 - - -
CYP1A2 substrate
 - - -
CYP2C19 inhibitor
 - - -
CYP2C19 substrate
 - - -
CYP2C9 inhibitor
 - - -
CYP2C9 substrate
 - - -
CYP2D6 inhibitor
 - -
CYP2D6 substrate
 - - -
CYP3A4 inhibitor
 - - -
CYP3A4 substrate
 ++
CYP2B6 inhibitor
 -
CYP2B6 substrate
 - - -
CYP2C8 inhibitor
 - - -
HLM Stability
 ++
 
Excretion
CLplasma
 15.453
 
T1/2
 1.247
Toxicity
DILI
 +
 
Rat Oral Acute Toxicity
 -
 
FDAMDD
 ++
 
Respiratory
 ++
 
Human Hepatotoxicity
 +
 
Ototoxicity
 +
 
Drug-induced Nephrotoxicity
 ++
 
Drug-induced Neurotoxicity
 +
 
Hematotoxicity
 - -
 
Genotoxicity
 - -
 
Tips: 1. For the classification endpoints, the prediction probability values are transformed into six symbols: 0-0.1 (- - -), 0.1-0.3 (- -), 0.3-0.5 (-), 0.5-0.7 (+), 0.7-0.9 (++), and 0.9-1.0 (+++). 2. Additionally, the corresponding relationships of the three labels are as follows: excellent; medium; poor.
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C27H41NO2
PubChem CID
442972
Canonical SMILES
CC1CC2C(C(C3(O2)CCC4C5CC=C6CC(CCC6(C5CC4=C3C)C)O)C)NC1
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
InChIKey
QASFUMOKHFSJGL-LAFRSMQTSA-N
CAS Number
CAS 4449-51-8
ChEBI ID
CHEBI:4021
Herb ID
HBIN022330
SymMap ID
SMIT10216
TCMSP ID
MOL009027
TTD Drug ID
D05UKJ
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Drug(s) Whose Efficacy can be Enhanced by This NP
          Tamoxifen      Breast cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression Gli1  Molecule Info 
Pathway MAP
                    In-vitro Model MCF-7 CVCL_0031 Invasive breast carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Combination of cyclopamine and tamoxifen promotes survival and migration of mcf-7 breast cancer cells--interaction of hedgehog-gli and estrogen receptor signaling pathways.
          Erlotinib      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression POU5F1  Molecule Info 
Pathway MAP
Down-regulation Expression PROM1  Molecule Info 
Pathway MAP
                    In-vitro Model Cells derived from glioblastoma patients Glioblastoma Homo sapiens
                    Experimental
                    Result(s)		 Synergic efficiency for erlotinib-cyclopamine association and provide a suitable in vitro model to explore drug combinations on GBM cells.
          Gefitinib      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
                    In-vitro Model PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone.
          Docetaxel + Gefitinib     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
                    In-vitro Model LNCaP CVCL_0395 Prostate carcinoma Homo sapiens
DU145 CVCL_0105 Prostate carcinoma Homo sapiens
PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Combined use of inhibitors of EGF-EGFR and hedgehog signaling with docetaxel could represent a more promising strategy for treatment in patients with metastatic and androgen-independent prostate cancer.
    β. A List of Drug(s) Whose Resistance can be Reversed by This NP
          Temozolomide      Brain cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression Gli1  Molecule Info 
Pathway MAP
                    In-vitro Model U-87MG ATCC CVCL_0022 Glioblastoma Homo sapiens
                    Experimental
                    Result(s)		 Combination of TMZ with micellarized Cyp is a promising strategy for exerting different functions of drugs for tumor treatment.
          TNF-related apoptosis inducing ligand      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression TRAIL-R2  Molecule Info 
Pathway MAP
                    Experimental
                    Result(s)		 Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation.
          Gemcitabine      Solid tumour/cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression Gli1  Molecule Info 
Pathway MAP
                    In-vitro Model SW1990 CVCL_1723 Pancreatic adenocarcinoma Homo sapiens
CFPAC-1 CVCL_1119 Cystic fibrosis Homo sapiens
                    Experimental
                    Result(s)		 Gemcitabine-resistant pancreatic cancer cells highly express CSCs markers and some of the HH members, and inhibition of HH by cyclopamine is an effective method of reversing gemcitabine resistance in pancreatic cancer.
Target and Pathway
Target(s) Smoothened homolog (SMO)  Molecule Info  [9]
KEGG Pathway Hedgehog signaling pathway Click to Show/Hide
2 Pathways in cancer
3 Proteoglycans in cancer
4 Basal cell carcinoma
Panther Pathway Hedgehog signaling pathway Click to Show/Hide
Pathway Interaction Database Signaling events mediated by the Hedgehog family Click to Show/Hide
2 Hedgehog signaling events mediated by Gli proteins
Reactome Class B/2 (Secretin family receptors) Click to Show/Hide
2 Hedgehog 'off' state
3 Activation of SMO
WikiPathways Hedgehog Signaling Pathway Click to Show/Hide
2 Hair Follicle Development: Organogenesis (Part 2 of 3)
3 Hair Follicle Development: Induction (Part 1 of 3)
4 Integrated Pancreatic Cancer Pathway
5 GPCR ligand binding
6 GPCRs, Other
References
Reference 1 Cyclopamine functions as a suppressor of benign prostatic hyperplasia by inhibiting epithelial and stromal cell proliferation via suppression of the Hedgehog signaling pathway. Int J Mol Med. 2020 Jul;46(1):311-319.
Reference 2 Combination of cyclopamine and tamoxifen promotes survival and migration of mcf-7 breast cancer cells--interaction of hedgehog-gli and estrogen receptor signaling pathways. PLoS One. 2014 Dec 12;9(12):e114510.
Reference 3 Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures. Neuro Oncol. 2012 Dec;14(12):1441-51.
Reference 4 Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int J Cancer. 2006 Feb 15;118(4):1022-31.
Reference 5 Combination therapy with micellarized cyclopamine and temozolomide attenuate glioblastoma growth through Gli1 down-regulation. Oncotarget. 2017 Jun 27;8(26):42495-42509.
Reference 6 Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation. Int J Biochem Cell Biol. 2017 Aug;89:147-156.
Reference 7 Cyclopamine reverts acquired chemoresistance and down-regulates cancer stem cell markers in pancreatic cancer cell lines. Swiss Med Wkly. 2011 May 31;141:w13208.
Reference 8 Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol Cancer Ther. 2007 Mar;6(3):967-78.
Reference 9 Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signali... Bioorg Med Chem Lett. 2009 Jan 15;19(2):328-31.
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