Identification

Name
Dicoumarol
Accession Number
DB00266  (APRD00761)
Type
Small Molecule
Groups
Approved
Description

An oral anticoagulant that interferes with the metabolism of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases. [PubChem]

Structure
Thumb
Synonyms
  • 3,3'-Methylen-bis(4-hydroxy-cumarin)
  • 3,3'-Methylene-bis(4-hydroxycoumarine)
  • 3,3'-Methylenebis(4-hydroxy-1,2-benzopyrone)
  • 3,3'-Methylenebis(4-hydroxy-2H-1-benzopyran-2-one)
  • 3,3'-Methylenebis(4-hydroxycoumarin)
  • bis-3,3'-(4-hydroxycoumarinyl)methane
  • bis-hydroxycoumarin
  • Bis(4-hydroxycoumarin-3-yl)methane
  • di-(4-hydroxy-3-coumarinyl)methane
  • Dicoumarol
  • Dicoumarolum
  • Dicumarol
External IDs
NSC-17860 / NSC-221570 / NSC-41834
Categories
UNII
7QID3E7BG7
CAS number
66-76-2
Weight
Average: 336.295
Monoisotopic: 336.063388116
Chemical Formula
C19H12O6
InChI Key
DOBMPNYZJYQDGZ-UHFFFAOYSA-N
InChI
InChI=1S/C19H12O6/c20-16-10-5-1-3-7-14(10)24-18(22)12(16)9-13-17(21)11-6-2-4-8-15(11)25-19(13)23/h1-8,20-21H,9H2
IUPAC Name
4-hydroxy-3-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2H-chromen-2-one
SMILES
OC1=C(CC2=C(O)C3=C(OC2=O)C=CC=C3)C(=O)OC2=C1C=CC=C2

Pharmacology

Indication

For decreasing blood clotting. Often used along with heparin for treatment of deep vein thrombosis.

Pharmacodynamics

Dicumarol is an coumarin-like compound found in sweet clover. It is used as an oral anticoagulant and acts by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors (prothrombin and factors VII, IX, and X). It is also used in biochemical experiments as an inhibitor of reductases.

Mechanism of action

Dicumarol inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

TargetActionsOrganism
AVitamin K epoxide reductase complex subunit 1
inhibitor
Human
UNAD(P)H dehydrogenase [quinone] 1
inhibitor
Human
UQuinone oxidoreductase
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

LD50=233 mg/kg (orally in mice); LD50=250 mg/kg (orally in rats)

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Dicumarol Action PathwayDrug action
Dicoumarol Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(1,2,6,7-3H)TestosteroneThe therapeutic efficacy of Dicoumarol can be increased when used in combination with (1,2,6,7-3H)Testosterone.
(R)-warfarinThe risk or severity of bleeding can be increased when Dicoumarol is combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Dicoumarol can be decreased when combined with (S)-Warfarin.
1-TestosteroneThe therapeutic efficacy of Dicoumarol can be increased when used in combination with 1-Testosterone.
18-methyl-19-nortestosteroneThe therapeutic efficacy of Dicoumarol can be increased when used in combination with 18-methyl-19-nortestosterone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Dicoumarol.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Dicoumarol.
3,5-diiodothyropropionic acid3,5-diiodothyropropionic acid may increase the anticoagulant activities of Dicoumarol.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Dicoumarol.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Dicoumarol is combined with 4-hydroxycoumarin.
Food Interactions
Not Available

References

General References
  1. Cullen JJ, Hinkhouse MM, Grady M, Gaut AW, Liu J, Zhang YP, Weydert CJ, Domann FE, Oberley LW: Dicumarol inhibition of NADPH:quinone oxidoreductase induces growth inhibition of pancreatic cancer via a superoxide-mediated mechanism. Cancer Res. 2003 Sep 1;63(17):5513-20. [PubMed:14500388]
  2. Mironov AA, Colanzi A, Polishchuk RS, Beznoussenko GV, Mironov AA Jr, Fusella A, Di Tullio G, Silletta MG, Corda D, De Matteis MA, Luini A: Dicumarol, an inhibitor of ADP-ribosylation of CtBP3/BARS, fragments golgi non-compact tubular zones and inhibits intra-golgi transport. Eur J Cell Biol. 2004 Jul;83(6):263-79. [PubMed:15511084]
  3. Abdelmohsen K, Stuhlmann D, Daubrawa F, Klotz LO: Dicumarol is a potent reversible inhibitor of gap junctional intercellular communication. Arch Biochem Biophys. 2005 Feb 15;434(2):241-7. [PubMed:15639223]
  4. Thanos CG, Liu Z, Reineke J, Edwards E, Mathiowitz E: Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride. Pharm Res. 2003 Jul;20(7):1093-100. [PubMed:12880296]
External Links
Human Metabolome Database
HMDB0014411
KEGG Drug
D03798
KEGG Compound
C00796
PubChem Compound
54676038
PubChem Substance
46505536
ChemSpider
10183330
BindingDB
35525
ChEBI
4513
ChEMBL
CHEMBL1466
Therapeutic Targets Database
DAP000768
PharmGKB
PA449298
Wikipedia
Dicumarol
ATC Codes
B01AA01 — Dicoumarol
MSDS
Download (64.7 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
  • Eli lilly and co
  • Abbott laboratories pharmaceutical products div
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)290 °CPhysProp
water solubility128 mg/LNot Available
logP2.07HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.0662 mg/mLALOGPS
logP1.54ALOGPS
logP-1.6ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)-12ChemAxon
pKa (Strongest Basic)-3.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area93.06 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity89.19 m3·mol-1ChemAxon
Polarizability32.32 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8724
Blood Brain Barrier+0.8343
Caco-2 permeable-0.5899
P-glycoprotein substrateNon-substrate0.5073
P-glycoprotein inhibitor INon-inhibitor0.9304
P-glycoprotein inhibitor IINon-inhibitor0.8972
Renal organic cation transporterNon-inhibitor0.8982
CYP450 2C9 substrateNon-substrate0.8264
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.7557
CYP450 1A2 substrateNon-inhibitor0.7905
CYP450 2C9 inhibitorInhibitor0.8948
CYP450 2D6 inhibitorNon-inhibitor0.9681
CYP450 2C19 inhibitorNon-inhibitor0.6071
CYP450 3A4 inhibitorNon-inhibitor0.9098
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9165
Ames testNon AMES toxic0.9048
CarcinogenicityNon-carcinogens0.9549
BiodegradationNot ready biodegradable0.8347
Rat acute toxicity3.1251 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9269
hERG inhibition (predictor II)Non-inhibitor0.9435
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (9.73 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-0079-6914000000-95659ff5087535a07662
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 4-hydroxycoumarins. These are coumarins that contain one or more hydroxyl groups attached to C4-position the coumarin skeleton.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Coumarins and derivatives
Sub Class
Hydroxycoumarins
Direct Parent
4-hydroxycoumarins
Alternative Parents
1-benzopyrans / Pyranones and derivatives / Benzenoids / Vinylogous acids / Heteroaromatic compounds / Lactones / Oxacyclic compounds / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
4-hydroxycoumarin / Benzopyran / 1-benzopyran / Pyranone / Pyran / Benzenoid / Heteroaromatic compound / Vinylogous acid / Lactone / Oxacycle
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
hydroxycoumarin (CHEBI:4513) / coumarins (C00796)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Vitamin-k-epoxide reductase (warfarin-sensitive) activity
Specific Function
Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the...
Gene Name
VKORC1
Uniprot ID
Q9BQB6
Uniprot Name
Vitamin K epoxide reductase complex subunit 1
Molecular Weight
18234.3 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Wallin R, Patrick SD, Ballard JO: Vitamin K antagonism of coumarin intoxication in the rat. Thromb Haemost. 1986 Apr 30;55(2):235-9. [PubMed:2424118]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Superoxide dismutase activity
Specific Function
The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vit...
Gene Name
NQO1
Uniprot ID
P15559
Uniprot Name
NAD(P)H dehydrogenase [quinone] 1
Molecular Weight
30867.405 Da
References
  1. Chen S, Wu K, Zhang D, Sherman M, Knox R, Yang CS: Molecular characterization of binding of substrates and inhibitors to DT-diaphorase: combined approach involving site-directed mutagenesis, inhibitor-binding analysis, and computer modeling. Mol Pharmacol. 1999 Aug;56(2):272-8. [PubMed:10419545]
  2. Jaiswal AK: Characterization and partial purification of microsomal NAD(P)H:quinone oxidoreductases. Arch Biochem Biophys. 2000 Mar 1;375(1):62-8. [PubMed:10683249]
  3. Joseph P, Jaiswal AK: A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Br J Cancer. 2000 Apr;82(7):1305-11. [PubMed:10755406]
  4. Floreani M, Napoli E, Palatini P: Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria. Biochem Pharmacol. 2000 Aug 15;60(4):601-5. [PubMed:10874136]
  5. Arriagada C, Dagnino-Subiabre A, Caviedes P, Armero JM, Caviedes R, Segura-Aguilar J: Studies of aminochrome toxicity in a mouse derived neuronal cell line: is this toxicity mediated via glutamate transmission? Amino Acids. 2000;18(4):363-73. [PubMed:10949919]
  6. Preusch PC, Smalley DM: Vitamin K1 2,3-epoxide and quinone reduction: mechanism and inhibition. Free Radic Res Commun. 1990;8(4-6):401-15. [PubMed:2113031]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Does not have alcohol dehydrogenase activity. Binds NADP and acts through a one-electron transfer process. Orthoquinones, such as 1,2-naphthoquinone or 9,10-phenanthrenequinone, are the best substr...
Gene Name
CRYZ
Uniprot ID
Q08257
Uniprot Name
Quinone oxidoreductase
Molecular Weight
35206.36 Da
References
  1. Evans PJ: Decreased intracellular proteolysis correlates with the maintenance of a specific isoenzyme of cytochrome P-450. Cell Biol Int. 1999;23(2):117-24. [PubMed:10561120]
  2. Audi SH, Bongard RD, Dawson CA, Siegel D, Roerig DL, Merker MP: Duroquinone reduction during passage through the pulmonary circulation. Am J Physiol Lung Cell Mol Physiol. 2003 Nov;285(5):L1116-31. Epub 2003 Jul 25. [PubMed:12882764]
  3. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y: The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry. 2006 May 23;45(20):6372-8. [PubMed:16700548]
  4. Maser E, Gebel T, Netter KJ: Carbonyl reduction of metyrapone in human liver. Biochem Pharmacol. 1991 Dec 11;42 Suppl:S93-8. [PubMed:1722672]
  5. Hao H, Wang G, Cui N, Li J, Xie L, Ding Z: Identification of a novel intestinal first pass metabolic pathway: NQO1 mediated quinone reduction and subsequent glucuronidation. Curr Drug Metab. 2007 Feb;8(2):137-49. [PubMed:17305492]

Enzymes

Details
1. Cytochrome P450 2C9
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Curator comments
In general, anticoagulants such as warfarin and coumarin derivatives are substrates of CYP2C9. Dicoumarol, a coumarin derivative, is likely metabolized by this enzyme.
General Function
Steroid 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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Militaru FC, Vesa SC, Pop TR, Buzoianu AD: Pharmacogenetics aspects of oral anticoagulants therapy. J Med Life. 2015 Apr-Jun;8(2):171-5. [PubMed:25866574]
  2. Limdi NA, Arnett DK, Goldstein JA, Beasley TM, McGwin G, Adler BK, Acton RT: Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenomics. 2008 May;9(5):511-26. doi: 10.2217/14622416.9.5.511. [PubMed:18466099]
  3. Fung E, Patsopoulos NA, Belknap SM, O'Rourke DJ, Robb JF, Anderson JL, Shworak NW, Moore JH: Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost. 2012 Nov;38(8):893-904. doi: 10.1055/s-0032-1328891. Epub 2012 Oct 6. [PubMed:23041981]
Kind
Protein
Organism
Rat
Pharmacological action
Unknown
Actions
Inhibitor
General 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.
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
Cyp2c6
Uniprot ID
P05178
Uniprot Name
Cytochrome P450 2C6
Molecular Weight
56002.315 Da
References
  1. Stiborova M, Levova K, Barta F, Sulc M, Frei E, Arlt VM, Schmeiser HH: The influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats. Mutagenesis. 2014 May;29(3):189-200. doi: 10.1093/mutage/geu004. Epub 2014 Mar 5. [PubMed:24598128]
Kind
Protein
Organism
Rat
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metabolizes testosterone mainly in positions 2 alpha and 16 alpha.
Specific Function
Arachidonic acid epoxygenase activity
Gene Name
Cyp2c11
Uniprot ID
P08683
Uniprot Name
Cytochrome P450 2C11
Molecular Weight
57180.595 Da
References
  1. Stiborova M, Levova K, Barta F, Sulc M, Frei E, Arlt VM, Schmeiser HH: The influence of dicoumarol on the bioactivation of the carcinogen aristolochic acid I in rats. Mutagenesis. 2014 May;29(3):189-200. doi: 10.1093/mutage/geu004. Epub 2014 Mar 5. [PubMed:24598128]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Rahman MH, Miyoshi T, Sukimoto K, Takadate A, Otagiri M: Interaction mode of dicumarol and its derivatives with human serum albumin, alpha 1-acid glycoprotein and asialo alpha 1-acid glycoprotein. J Pharmacobiodyn. 1992 Jan;15(1):7-16. [PubMed:1376777]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:40