Dicumarol
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Basic Info
| Common Name | Dicumarol(F04982) |
| 2D Structure | |
| Description | Dicumarol is only found in individuals that have used or taken this drug. It is an oral anticoagulant that interferes with the metabolism of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases. [PubChem] 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. |
| FRCD ID | F04982 |
| CAS Number | 66-76-2 |
| PubChem CID | 54676038 |
| Formula | C19H12O6 |
| IUPAC Name | 4-hydroxy-3-[(4-hydroxy-2-oxochromen-3-yl)methyl]chromen-2-one |
| 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 |
| Canonical SMILES | C1=CC=C2C(=C1)C(=C(C(=O)O2)CC3=C(C4=CC=CC=C4OC3=O)O)O |
| Isomeric SMILES | C1=CC=C2C(=C1)C(=C(C(=O)O2)CC3=C(C4=CC=CC=C4OC3=O)O)O |
| Wikipedia | Dicumarol |
| Synonyms |
dicumarol
dicoumarol
Bishydroxycoumarin
dicoumarin
66-76-2
melitoxin
Antitrombosin
Baracoumin
Dicoumal
Dicumarine
|
| Classifies |
Fungal Toxin
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Phenylpropanoids and polyketides |
| Class | Coumarins and derivatives |
| Subclass | Hydroxycoumarins |
| Intermediate Tree Nodes | Not available |
| Direct Parent | 4-hydroxycoumarins |
| Alternative Parents | |
| Molecular Framework | Aromatic heteropolycyclic compounds |
| Substituents | 4-hydroxycoumarin - Benzopyran - 1-benzopyran - Pyranone - Pyran - Benzenoid - Heteroaromatic compound - Vinylogous acid - Lactone - Oxacycle - Organoheterocyclic compound - Organic oxygen compound - Hydrocarbon derivative - Organooxygen compound - Organic oxide - Aromatic heteropolycyclic compound |
| 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. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 336.299 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 2 |
| Complexity | 605 |
| Monoisotopic Mass | 336.063 |
| Exact Mass | 336.063 |
| XLogP | 2.6 |
| Formal Charge | 0 |
| Heavy Atom Count | 25 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB+ | 0.8343 |
| Human Intestinal Absorption | HIA+ | 0.8724 |
| Caco-2 Permeability | Caco2- | 0.5899 |
| P-glycoprotein Substrate | Non-substrate | 0.5073 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.9304 |
| Non-inhibitor | 0.8972 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.8982 |
| Distribution | ||
| Subcellular localization | Mitochondria | 0.8402 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.8264 |
| CYP450 2D6 Substrate | Non-substrate | 0.9116 |
| CYP450 3A4 Substrate | Non-substrate | 0.7557 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.7905 |
| CYP450 2C9 Inhibitor | Inhibitor | 0.8948 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9681 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.6071 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.9098 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.9165 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9269 |
| Non-inhibitor | 0.9435 | |
| AMES Toxicity | Non AMES toxic | 0.9048 |
| Carcinogens | Non-carcinogens | 0.9549 |
| Fish Toxicity | High FHMT | 0.9388 |
| Tetrahymena Pyriformis Toxicity | High TPT | 0.8983 |
| Honey Bee Toxicity | High HBT | 0.6423 |
| Biodegradation | Not ready biodegradable | 0.8347 |
| Acute Oral Toxicity | II | 0.7149 |
| Carcinogenicity (Three-class) | Non-required | 0.6978 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -3.1724 | LogS |
| Caco-2 Permeability | 0.3421 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 3.1251 | LD50, mol/kg |
| Fish Toxicity | 0.5835 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | 0.6130 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| Synergistic cytotoxicity of Delta(9)-tetrahydrocannabinol and butylated hydroxyanisole. | Toxicol Lett | 2002 Jul 21 | 12119125 |
| Evaluation of vitamin K3 feed additive for prevention of sweet clover disease. | J Vet Diagn Invest | 1989 Apr | 2484931 |
| Liver and fecal bishydroxycoumarin following repeated toxic oral bishydroxycoumarin administration in ground squirrels. | Toxicol Appl Pharmacol | 1971 Jun | 4105823 |
Targets
- 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 gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.
- Gene Name:
- VKORC1
- Uniprot ID:
- Q9BQB6
- Molecular Weight:
- 18234.3 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
- 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 substrates (in vitro). May act in the detoxification of xenobiotics. Interacts with (AU)-rich elements (ARE) in the 3'-UTR of target mRNA species. Enhances the stability of mRNA coding for BCL2. NADPH binding interferes with mRNA binding.
- Gene Name:
- CRYZ
- Uniprot ID:
- Q08257
- Molecular Weight:
- 35206.36 Da
References
- 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. [10561120 ]
- Specific Function:
- Keratin-binding protein required for epithelial cell polarization. Involved in apical junction complex (AJC) assembly via its interaction with PARD3. Required for ciliogenesis.
- Gene Name:
- FBF1
- Uniprot ID:
- Q8TES7
- Molecular Weight:
- 125445.19 Da
References
- Vallner JJ, Perrin JH, Wold S: Comparison of graphical and computerized methods for calculating binding parameters for two strongly bound drugs to human serum albumin. J Pharm Sci. 1976 Aug;65(8):1182-7. [62049 ]
- General Function:
- G-protein coupled receptor activity
- Specific Function:
- Acts as a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. The activity of this receptor is mediated by G-proteins that elicit calcium mobilization and inositol phosphate production through G(qi/o) proteins.
- Gene Name:
- GPR35
- Uniprot ID:
- Q9HC97
- Molecular Weight:
- 34071.89 Da
References
- Thimm D, Funke M, Meyer A, Muller CE: 6-Bromo-8-(4-[(3)H]methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic Acid: a powerful tool for studying orphan G protein-coupled receptor GPR35. J Med Chem. 2013 Sep 12;56(17):7084-99. doi: 10.1021/jm4009373. Epub 2013 Aug 15. [23888932 ]
- General Function:
- Serine-type endopeptidase activity
- Specific Function:
- Likely to represent a ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RXXX[KR]R consensus motif.
- Gene Name:
- PCSK7
- Uniprot ID:
- Q16549
- Molecular Weight:
- 86246.44 Da
References
- de Oliveira CM, Silva GH, Regasini LO, Flausino O, Lopez SN, Abissi BM, Berlinck RG, Sette LD, Bonugli-Santos RC, Rodrigues A, Bolzani Vda S, Araujo AR: Xylarenones C-E from an endophytic fungus isolated from Alibertia macrophylla. J Nat Prod. 2011 Jun 24;74(6):1353-7. doi: 10.1021/np1005983. Epub 2011 Apr 21. [21510613 ]
- 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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
- Gene Name:
- CYP2C9
- Uniprot ID:
- P11712
- Molecular Weight:
- 55627.365 Da
References
- Afzelius L, Zamora I, Masimirembwa CM, Karlen A, Andersson TB, Mecucci S, Baroni M, Cruciani G: Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors. J Med Chem. 2004 Feb 12;47(4):907-14. [14761192 ]
- 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 vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.
- Gene Name:
- NQO1
- Uniprot ID:
- P15559
- Molecular Weight:
- 30867.405 Da
- Mechanism of Action:
- Dicoumarol is an anticoagulant that competitively inhibits vitamin K, preventing the formation of prothrombin. It does this by inhibiting the enzyme NADH:quinone oxidoreductase-1, which is required for the reduction of vitamin K to its hydroquinone. Reduced vitamin K is a cofactor needed in the conversion of prothrombin precursor protein to active prothrombin, an essential protein for blood clotting. In addition, inhibition of NADH:quinone oxidoreductase-1 induces the generation of superoxide anion radicals that inhibit cell growth. Dicoumarol can also potently and reversible inhibit gap junctional intercellular communication, though the precise mechanism is unknown.
References
- 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. [14500388 ]