2-Methoxyestradiol

Identification

Generic Name
2-Methoxyestradiol
DrugBank Accession Number
DB02342
Background

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 and preclinical studies suggest that 2ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis.

Type
Small Molecule
Groups
Investigational
Structure
Weight
Average: 302.4079
Monoisotopic: 302.188194698
Chemical Formula
C19H26O3
Synonyms
  • 2-Hydroxyestradiol 2-methyl ether
  • 2-Hydroxyestradol 2-methyl ether
  • 2-ME2
  • 2-methoxy-17β-estradiol
  • 2-Methoxyestradiol-17beta
  • 2ME2

Pharmacology

Indication

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

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Contraindications & Blackbox Warnings
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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
UCatechol O-methyltransferaseNot AvailableHumans
UCytochrome P450 1A1Not AvailableHumans
UCytochrome P450 1B1Not AvailableHumans
UCytochrome P450 19A1Not AvailableHumans
UHypoxia-inducible factor 1-alphaNot AvailableHumans
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

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AmbroxolThe risk or severity of methemoglobinemia can be increased when 2-Methoxyestradiol is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when 2-Methoxyestradiol is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when 2-Methoxyestradiol is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when 2-Methoxyestradiol is combined with Benzyl alcohol.
BupivacaineThe risk or severity of methemoglobinemia can be increased when 2-Methoxyestradiol is combined with Bupivacaine.
Food Interactions
Not Available

Products

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International/Other Brands
Panzem / Panzem NCD / Pulmolar

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
6I2QW73SR5
CAS number
362-07-2
InChI Key
CQOQDQWUFQDJMK-SSTWWWIQSA-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
(1S,3aS,3bR,9bS,11aS)-8-methoxy-11a-methyl-1H,2H,3H,3aH,3bH,4H,5H,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,7-diol
SMILES
[H][C@@]12CC[C@H](O)[C@@]1(C)CC[C@]1([H])C3=C(CC[C@@]21[H])C=C(O)C(OC)=C3

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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  7. Lakhani NJ, Sarkar MA, Venitz J, Figg WD: 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy. 2003 Feb;23(2):165-72. [Article]
Human Metabolome Database
HMDB0000405
KEGG Compound
C05302
PubChem Compound
16760554
PubChem Substance
175426854
ChemSpider
59788
BindingDB
50060957
ChEBI
28955
ChEMBL
CHEMBL299613
ZINC
ZINC000003818826
PharmGKB
PA13496724
PDBe Ligand
ESM
Wikipedia
2-Methoxyestradiol
PDB Entries
1lhw

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCarcinoid Tumors1
2CompletedTreatmentMetastatic Renal Cell Carcinoma ( mRCC)1
2CompletedTreatmentOvarian Cancer1
2CompletedTreatmentPlateau Phase Multiple Myeloma / Relapsed Multiple Myeloma1
2CompletedTreatmentProstate Cancer1

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
Polarizability35.2 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
GC-MS Spectrum - GC-MS (2 TMS)GC-MSsplash10-016s-2792200000-4c8c5cfcb17a537e5130
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-00dr-1190000000-c0b6f1d0f5e462b22c79
GC-MS Spectrum - GC-MSGC-MSsplash10-016s-2792200000-4c8c5cfcb17a537e5130
MS/MS Spectrum - Quattro_QQQ 10V, PositiveLC-MS/MSsplash10-0udi-0900000000-51addcf0be873acf4568
MS/MS Spectrum - Quattro_QQQ 25V, PositiveLC-MS/MSsplash10-0udi-0900000000-9189876ead18b5520cfc
MS/MS Spectrum - Quattro_QQQ 40V, PositiveLC-MS/MSsplash10-0ue9-0900000000-c60cd007c37d58b43c6f
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udr-0059000000-9036ddd6228589ba4743
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0009000000-b1e1c829d716eae08bd6
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udr-1793000000-8b908b684968ed74ea7a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0009000000-dbb1040481382d68ada8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-1000-0091000000-be3bb859f3b191587465
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-117s-4930000000-96d0615b0804c8389810
1H NMR Spectrum1D NMRNot Applicable
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-184.3108702
predicted
DarkChem Lite v0.1.0
[M-H]-184.3913702
predicted
DarkChem Lite v0.1.0
[M-H]-182.61668
predicted
DeepCCS 1.0 (2019)
[M+H]+186.4690702
predicted
DarkChem Lite v0.1.0
[M+H]+185.8527702
predicted
DarkChem Lite v0.1.0
[M+H]+185.01224
predicted
DeepCCS 1.0 (2019)
[M+Na]+183.9649702
predicted
DarkChem Lite v0.1.0
[M+Na]+184.1157702
predicted
DarkChem Lite v0.1.0
[M+Na]+190.92476
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
Kind
Protein
Organism
Humans
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. [Article]
  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. [Article]

Carriers

Kind
Protein
Organism
Humans
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 at June 13, 2005 13:24 / Updated at January 14, 2023 19:03