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Identification
Name2-Methoxyestradiol
Accession NumberDB02342  (EXPT01362)
TypeSmall Molecule
GroupsInvestigational
Description2-Methoxyestradiol (2ME2) is a drug that prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis). It has undergone Phase 1 clinical trials against breast cancers. Preclinical models also suggest that 2ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis. [Wikipedia]
Structure
Thumb
Synonyms
2-Hydroxyestradiol 2-methyl ether
2-Hydroxyestradol 2-methyl ether
2-MeOE2
2-methoxy-17beta-estradiol
2-methoxyestra-1(10),2,4-triene-3,17-diol
2-Methoxyestradiol-17beta
2ME2
ESM
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
PanzemNot Available
Panzem NCDNot Available
PulmolarNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII6I2QW73SR5
CAS number362-07-2
WeightAverage: 302.4079
Monoisotopic: 302.188194698
Chemical FormulaC19H26O3
InChI KeyInChIKey=CQOQDQWUFQDJMK-WRWXEFHESA-N
InChI
InChI=1S/C19H26O3/c1-19-8-7-12-13(15(19)5-6-18(19)21)4-3-11-9-16(20)17(22-2)10-14(11)12/h9-10,12-13,15,18,20-21H,3-8H2,1-2H3/t12?,13?,15?,18-,19-/m0/s1
IUPAC Name
(14S,15S)-4-methoxy-15-methyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-2,4,6-triene-5,14-diol
SMILES
COC1=C(O)C=C2CCC3C4CC[[email protected]](O)[C@@]4(C)CCC3C2=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassEstrane steroids
Direct ParentEstrogens and derivatives
Alternative Parents
Substituents
  • Estrogen-skeleton
  • 17-hydroxysteroid
  • Hydroxysteroid
  • 3-hydroxysteroid
  • Phenanthrene
  • Tetralin
  • Methoxyphenol
  • Anisole
  • Alkyl aryl ether
  • Benzenoid
  • Cyclic alcohol
  • Secondary alcohol
  • Ether
  • Hydrocarbon derivative
  • Organooxygen compound
  • Alcohol
  • Aromatic homopolycyclic compound
Molecular FrameworkAromatic homopolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of breast cancer and inflammatory diseases such as rheumatoid arthritis.
Pharmacodynamics2-Methoxyestradiol belongs to the family of drugs called angiogenesis inhibitors. It also acts as a vasodilator.
Mechanism of action2-Methoxyestradiol is an angiogenesis inhibitor, and has been shown to attack both tumor cells and their blood supply in preclinical testing. 2-methoxyestradiol is a naturally occurring estrogen metabolite but has no undesired estrogenic activity.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding2ME2 was found to bind in decreasing order to plasma>albumin>alpha1-acid glycoprotein>sex-hormone-binding globulin. Plasma concentration-time profiles of total 2ME2 and unbound 2ME2 concentrations in a patient with cancer receiving 2ME2 as a single oral dose were parallel to each other. Thus, indicating that plasma protein binding is not an important consideration in pharmacokinetic monitoring of 2ME2.
Metabolism

In vivo metabolism, assessed using 24-h collections of urine from cancer patients treated with 2ME2 revealed that <0.01% of the total administered dose of 2ME2 is excreted unchanged in urine and about 1% excreted as glucuronides. Collectively, this suggests that glucuronidation and subsequent urinary excretion are elimination pathways for 2ME2.

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9952
Blood Brain Barrier+0.8506
Caco-2 permeable+0.8415
P-glycoprotein substrateSubstrate0.7829
P-glycoprotein inhibitor INon-inhibitor0.7228
P-glycoprotein inhibitor IINon-inhibitor0.817
Renal organic cation transporterNon-inhibitor0.8176
CYP450 2C9 substrateNon-substrate0.7967
CYP450 2D6 substrateNon-substrate0.8076
CYP450 3A4 substrateSubstrate0.7532
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9345
CYP450 2C19 inhibitorNon-inhibitor0.8521
CYP450 3A4 inhibitorNon-inhibitor0.8308
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8483
Ames testNon AMES toxic0.8878
CarcinogenicityNon-carcinogens0.9109
BiodegradationNot ready biodegradable0.9879
Rat acute toxicity1.8598 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.965
hERG inhibition (predictor II)Inhibitor0.7189
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00968 mg/mLALOGPS
logP3.7ALOGPS
logP3.59ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)10.29ChemAxon
pKa (Strongest Basic)-0.88ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area49.69 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity86.37 m3·mol-1ChemAxon
Polarizability35.21 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Schumacher G, Hoffmann J, Cramer T, Spinelli A, Jacob D, Bahra M, Pratschke J, Pfitzmann R, Schmidt S, Lage H: Antineoplastic activity of 2-methoxyestradiol in human pancreatic and gastric cancer cells with different multidrug-resistant phenotypes. J Gastroenterol Hepatol. 2007 Sep;22(9):1469-73. Epub 2007 Jul 20. [PubMed:17645459 ]
  2. Sutherland TE, Anderson RL, Hughes RA, Altmann E, Schuliga M, Ziogas J, Stewart AG: 2-Methoxyestradiol--a unique blend of activities generating a new class of anti-tumour/anti-inflammatory agents. Drug Discov Today. 2007 Jul;12(13-14):577-84. Epub 2007 Jun 26. [PubMed:17631253 ]
  3. Fong YC, Yang WH, Hsu SF, Hsu HC, Tseng KF, Hsu CJ, Lee CY, Scully SP: 2-methoxyestradiol induces apoptosis and cell cycle arrest in human chondrosarcoma cells. J Orthop Res. 2007 Aug;25(8):1106-14. [PubMed:17415781 ]
  4. Eichenlaub-Ritter U, Winterscheidt U, Vogt E, Shen Y, Tinneberg HR, Sorensen R: 2-methoxyestradiol induces spindle aberrations, chromosome congression failure, and nondisjunction in mouse oocytes. Biol Reprod. 2007 May;76(5):784-93. Epub 2007 Jan 17. [PubMed:17229934 ]
  5. Lakhani NJ, Sparreboom A, Xu X, Veenstra TD, Venitz J, Dahut WL, Figg WD: Characterization of in vitro and in vivo metabolic pathways of the investigational anticancer agent, 2-methoxyestradiol. J Pharm Sci. 2007 Jul;96(7):1821-31. [PubMed:17252610 ]
  6. Lakhani N, Sparreboom A, Venitz J, Dahut WL, Figg WD: Plasma protein binding of the investigational anticancer agent 2-methoxyestradiol. Anticancer Drugs. 2006 Sep;17(8):977-83. [PubMed:16940808 ]
  7. Lakhani NJ, Sarkar MA, Venitz J, Figg WD: 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy. 2003 Feb;23(2):165-72. [PubMed:12587805 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.
BevacizumabBevacizumab may increase the cardiotoxic activities of 2-Methoxyestradiol.
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with 2-Methoxyestradiol.
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of 2-Methoxyestradiol.
DeslanosideDeslanoside may decrease the cardiotoxic activities of 2-Methoxyestradiol.
DigitoxinDigitoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.
DigoxinDigoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with 2-Methoxyestradiol.
OuabainOuabain may decrease the cardiotoxic activities of 2-Methoxyestradiol.
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with 2-Methoxyestradiol.
TrastuzumabTrastuzumab may increase the cardiotoxic activities of 2-Methoxyestradiol.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Ubiquitin protein ligase binding
Specific Function:
Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essentia...
Gene Name:
HIF1A
Uniprot ID:
Q16665
Molecular Weight:
92669.595 Da
References
  1. Zhou D, Matchett GA, Jadhav V, Dach N, Zhang JH: The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats. Neurol Res. 2008 Apr;30(3):268-71. Epub 2007 Aug 22. [PubMed:17716391 ]
  2. Dai Y, Xu M, Wang Y, Pasha Z, Li T, Ashraf M: HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia. J Mol Cell Cardiol. 2007 Jun;42(6):1036-44. Epub 2007 Apr 6. [PubMed:17498737 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
O-methyltransferase activity
Specific Function:
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol.
Gene Name:
COMT
Uniprot ID:
P21964
Molecular Weight:
30036.77 Da
References
  1. Parvez S, Parvez SH, Youdim MB: Variation in activity of monoamine metabolizing enzymes in rat liver during pregnancy. Br J Pharmacol. 1975 Feb;53(2):241-6. [PubMed:1170911 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Vitamin d 24-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 Da
References
  1. Dawling S, Roodi N, Parl FF: Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Cancer Res. 2003 Jun 15;63(12):3127-32. [PubMed:12810639 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Oxygen binding
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics. Preferentially oxidizes 17beta-estradiol to the carcinogenic 4-hydroxy derivative, and a variety of procarcinogenic compou...
Gene Name:
CYP1B1
Uniprot ID:
Q16678
Molecular Weight:
60845.33 Da
References
  1. Dawling S, Roodi N, Parl FF: Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1. Cancer Res. 2003 Jun 15;63(12):3127-32. [PubMed:12810639 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Oxygen binding
Specific Function:
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name:
CYP19A1
Uniprot ID:
P11511
Molecular Weight:
57882.48 Da
References
  1. Purohit A, Singh A, Ghilchik MW, Reed MJ: Inhibition of tumor necrosis factor alpha-stimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol. Biochem Biophys Res Commun. 1999 Jul 22;261(1):214-7. [PubMed:10405348 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Androgen binding
Specific Function:
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration.
Gene Name:
SHBG
Uniprot ID:
P04278
Molecular Weight:
43778.755 Da
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23