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Identification
Name Estramustine
Accession Number DB01196 (APRD00625)
Type small molecule
Groups approved
Description

A nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasms; also has radiation protective properties. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Estramustin Sodium Phosphate
  • Estramustina [INN-Spanish]
  • Estramustine Sodium Phosphate
  • Estramustinum [INN-Latin]
Brand names
  • Emcyt
  • Estracyt
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antineoplastic Agents, Hormonal
  • Radiation-Protective Agents
  • Antineoplastic Agents, Alkylating
CAS number 2998-57-4
Weight Average: 440.403
Monoisotopic: 439.168099277
Chemical Formula C23H31Cl2NO3
InChI Key InChIKey=FRPJXPJMRWBBIH-UHFFFAOYSA-N
InChI
InChI=1S/C23H31Cl2NO3/c1-23-9-8-18-17-5-3-16(29-22(28)26(12-10-24)13-11-25)14-15(17)2-4-19(18)20(23)6-7-21(23)27/h3,5,14,18-21,27H,2,4,6-13H2,1H3
Plain Text
IUPAC Name
14-hydroxy-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2(7),3,5-trien-5-yl N,N-bis(2-chloroethyl)carbamate
SMILES
CC12CCC3C(CCC4=C3C=CC(OC(=O)N(CCCl)CCCl)=C4)C1CCC2O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Hydroxy Compounds
  • Naphthalenes
  • Carbamates and Derivatives
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Phenanthrenes
  • Alkyl Halides
  • Aromatic compounds
  • Anisoles
  • Nitrogen Mustards
  • Steroids and Steroid Derivatives
  • Alcohols and Polyols
  • Cyclohexenes and Derivatives
  • Phenyl Esters
Pharmacology
Indication For the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate
Pharmacodynamics Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nitrogen mustard. In vivo, the nitrogen-mustard moiety becomes active and participates in alkylation of DNA or other cellular components.. This causes DNA damage in rapidly dividing cancerous cells leading to cell death and ideally, tumor shrinkage.
Mechanism of action Estramustine is a derivative of estradiol with a nitrogen mustard moiety. This gives it alkylating properties. In vivo, the nitrogen mustard component is active and can alklyate DNA and other cellular components (such as tubulin components) of rapidly dividing cells. This causes DNA strandbreaks or misscoding events. This leads to apoptosis and cell death. Also, due to the drugs estrogen component, it can bind more selectively to active estrogen receptors.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism
Route of elimination The metabolic urinary patterns of the estradiol moiety of estramustine phosphate and estradiol itself are very similar, although the metabolites derived from estramustine phosphate are excreted at a slower rate.
Half life 20 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pharmacia and upjohn co
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Prices
Unit description Cost Unit
Emcyt 140 mg capsule 6.55 USD capsule
Patents Not Available
Properties
State solid
Melting point 104.5 oC
Experimental Properties
Property Value Source
logP 5.7 PhysProp
Predicted Properties
Property Value Source
water solubility 3.85e-04 g/l ALOGPS
logP 4.97 ALOGPS
logP 5.10 ChemAxon Molconvert
logS -6.06 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 49.77 ChemAxon Molconvert
rotatable bond count 6 ChemAxon Molconvert
refractivity 116.21 ChemAxon Molconvert
polarizability 48.50 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D04066 Link_out
KEGG Compound C11228 Link_out
PubChem Compound 18140 Link_out
PubChem Substance 46508765 Link_out
ChemSpider 17134 Link_out
BindingDB 50025102 Link_out
ChEBI 4868 Link_out
ChEMBL 4868 Link_out
Therapeutic Targets Database DAP001307 Link_out
Drug Product Database 2063794 Link_out
RxList http://www.rxlist.com/cgi/generic2/estramustine.htm Link_out
Drugs.com http://www.drugs.com/cdi/estramustine.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Estramustine Link_out
ATC Codes
  • L01XX11
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Do not take with milk or milk products.
  • Take on an empty stomach.
Targets

1. Microtubule-associated protein 2

Pharmacological action: yes
Actions: antagonist

The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization. They also seem to have a stiffening effect on microtubules

Organism class: human
UniProt ID: P11137 Link_out
Gene: MAP2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Moraga D, Rivas-Berrios A, Farias G, Wallin M, Maccioni RB: Estramustine-phosphate binds to a tubulin binding domain on microtubule-associated proteins MAP-2 and tau. Biochim Biophys Acta. 1992 May 22;1121(1-2):97-103. Pubmed
  2. Stearns ME, Wang M, Sousa O: Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion. J Cell Sci. 1991 Jan;98 ( Pt 1):55-63. Pubmed
  3. Friden B, Rutberg M, Deinum J, Wallin M: The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Biochem Pharmacol. 1991 Aug 8;42(5):997-1006. Pubmed
  4. Burns RG: Stoichiometry of estramustine phosphate binding to MAP2 measured by the disassembly of chick brain MAP2:tubulin microtubules. Cell Motil Cytoskeleton. 1990;17(3):167-73. Pubmed
  5. Falconer MM, Vielkind U, Brown DL: Association of acetylated microtubules, vimentin intermediate filaments, and MAP 2 during early neural differentiation in EC cell culture. Biochem Cell Biol. 1989 Sep;67(9):537-44. Pubmed
  6. Tew KD: The mechanism of action of estramustine. Semin Oncol. 1983 Sep;10(3 Suppl 3):21-6. Pubmed

2. Microtubule-associated protein 1A

Pharmacological action: yes
Actions: antagonist

Structural protein involved in the filamentous cross- bridging between microtubules and other skeletal elements

Organism class: human
UniProt ID: P78559 Link_out
Gene: MAP1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Stearns ME, Wang M, Sousa O: Evidence that estramustine binds MAP-1A to inhibit type IV collagenase secretion. J Cell Sci. 1991 Jan;98 ( Pt 1):55-63. Pubmed

3. Estrogen receptor

Pharmacological action: yes
Actions: agonist

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues

Organism class: human
UniProt ID: P03372 Link_out
Gene: ESR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ferno M, Borg A, Ingvar C, Jonsson PE: Estrogen receptor and binding site for estramustine in metastatic malignant melanoma. Anticancer Res. 1987 Jul-Aug;7(4B):741-3. Pubmed
  2. Yoshizumi N: [The effects of site-directed chemotherapy due to E2 as a drug carrier to the human endometrial adenocarcinoma cells in vitro] Nippon Sanka Fujinka Gakkai Zasshi. 1985 Apr;37(4):637-45. Pubmed
  3. von Schoultz E, Carlstrom K, Henriksson R, Lagerlof B, Hansson J: Estramustine binding protein in primary tumours and metastases of malignant melanoma. Melanoma Res. 1994 Dec;4(6):401-5. Pubmed
  4. Tew KD: The mechanism of action of estramustine. Semin Oncol. 1983 Sep;10(3 Suppl 3):21-6. Pubmed

4. Estrogen receptor beta

Pharmacological action: yes
Actions: other/unknown

Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA- binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual

Organism class: human
UniProt ID: Q92731 Link_out
Gene: ESR2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ho SM: Estrogens and anti-estrogens: key mediators of prostate carcinogenesis and new therapeutic candidates. J Cell Biochem. 2004 Feb 15;91(3):491-503. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yang CP, Shen HJ, Horwitz SB: Modulation of the function of P-glycoprotein by estramustine. J Natl Cancer Inst. 1994 May 4;86(9):723-5. Pubmed
  2. Tiersten AD, Nelsen C, Talbot S, Vahdat L, Fine R, Troxel A, Brafman L, Shriberg L, Antman K, Petrylak DP: A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma. Cancer. 2003 Feb 1;97(3):537-44. Pubmed
  3. Smith CD, Zilfou JT, Zhang X, Hudes GR, Tew KD: Modulation of P-glycoprotein activity by estramustine is limited by binding to plasma proteins. Cancer. 1995 May 15;75(10):2597-604. Pubmed
  4. Speicher LA, Barone LR, Chapman AE, Hudes GR, Laing N, Smith CD, Tew KD: P-glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine. J Natl Cancer Inst. 1994 May 4;86(9):688-94. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:09

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.