2-Methoxyestradiol

Identification

Name
2-Methoxyestradiol
Accession Number
DB02342  (EXPT01362)
Type
Small Molecule
Groups
Investigational
Description

2-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
International/Other Brands
Panzem / Panzem NCD / Pulmolar
Categories
UNII
6I2QW73SR5
CAS number
362-07-2
Weight
Average: 302.4079
Monoisotopic: 302.188194698
Chemical Formula
C19H26O3
InChI Key
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)[[email protected]@]4(C)CCC3C2=C1

Pharmacology

Indication

For the treatment of breast cancer and inflammatory diseases such as rheumatoid arthritis.

Structured Indications
Not Available
Pharmacodynamics

2-Methoxyestradiol belongs to the family of drugs called angiogenesis inhibitors. It also acts as a vasodilator.

Mechanism of action

2-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.

TargetActionsOrganism
UHypoxia-inducible factor 1-alphaNot AvailableHuman
UCatechol O-methyltransferaseNot AvailableHuman
UCytochrome P450 1A1Not AvailableHuman
UCytochrome P450 1B1Not AvailableHuman
UCytochrome P450 19A1Not AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

2ME2 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 elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of 2-Methoxyestradiol.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with 2-Methoxyestradiol.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of 2-Methoxyestradiol.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with 2-Methoxyestradiol.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of 2-Methoxyestradiol.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with 2-Methoxyestradiol.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of 2-Methoxyestradiol.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of 2-Methoxyestradiol.Approved, Investigational
Food Interactions
Not Available

References

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
KEGG Compound
C05302
PubChem Compound
16760554
PubChem Substance
175426854
ChemSpider
21395883
ChEBI
28955
PharmGKB
PA13496724
HET
ESM
Wikipedia
2-Methoxyestradiol

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentRefractory Multiple Myeloma / Stage III Multiple Myeloma / Unspecified Adult Solid Tumor, Protocol Specific1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
2CompletedTreatmentMetastatic Renal Cell Carcinoma1
2CompletedTreatmentPlateau Phase Multiple Myeloma / Relapsed Multiple Myeloma1
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentRecurrent Glioblastoma Multiforme2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrogens and derivatives
Alternative Parents
3-hydroxysteroids / 17-hydroxysteroids / Phenanthrenes and derivatives / Tetralins / Anisoles / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Secondary alcohols / Cyclic alcohols and derivatives / Hydrocarbon derivatives
Substituents
Estrogen-skeleton / 3-hydroxysteroid / 17-hydroxysteroid / Hydroxysteroid / Phenanthrene / Tetralin / Anisole / 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Benzenoid
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not 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 transp...
Gene Name
HIF1A
Uniprot ID
Q16665
Uniprot Name
Hypoxia-inducible factor 1-alpha
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-DOP...
Gene Name
COMT
Uniprot ID
P21964
Uniprot Name
Catechol O-methyltransferase
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 un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
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 un...
Gene Name
CYP1B1
Uniprot ID
Q16678
Uniprot Name
Cytochrome P450 1B1
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
Uniprot Name
Aromatase
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...
Gene Name
SHBG
Uniprot ID
P04278
Uniprot Name
Sex hormone-binding globulin
Molecular Weight
43778.755 Da

Drug created on June 13, 2005 07:24 / Updated on November 09, 2017 03:12