66-76-2

Usage

Uses

Used in Pharmaceutical Industry:
DICUMAROL is used as an anticoagulant agent for preventing and treating thrombosis, thrombophlebitis, thromboembolism, and for preventing thrombo-formation in post-operational periods. It functions as a vitamin K antagonist, which is essential in the clotting process.
Used in Cancer Research:
DICUMAROL is used as an antiproliferative agent for various cancer cell lines, including pancreas, colon carcinoma, lymphocytic, and breast carcinoma cells. It inhibits stress-activated protein kinase (SAPK) and TNF-α and LPS-induced NF-κB activation in cells, suppressing JNK activation and exerting inhibitory effects on tumor growth and progression.
Used in Chemical Research:
DICUMAROL is used as a competitive inhibitor of NADH:quinone oxidoreductase (NQO1) in chemical research, with IC50 values of 2.6 and 404 nM in the absence and presence of 2 μM BSA, respectively. This property makes it a valuable compound for studying enzyme inhibition and related biochemical processes.
Physical Properties:
Appearance: White or milky white crystalline powder, slightly fragran
Solubility: Not dissolved in water, ethanol, and ether, slightly dissolved in chloroform, dissolved in alkali solution
Melting point: 287–293°C
It can exhibit blue or purple fluorescence in ultraviolet light.
Chemical Properties:
DICUMAROL is a hydroxycoumarin that is methane in which two hydrogens have each been substituted by a 4-hydroxycoumarin-3-yl group, resulting in a white fine crystalline powder.

History

In 1940, Karl Paul Link, a fertile scientist from the University of Wisconsin in the United States, first isolated the anticoagulant substance from the moldy alfalfa (Melilotus) and determined its structure. It is a kind of dicoumaroloid substance, combined by two molecules of coumarin substances. Since this material was found in the first few years, it has been used as a rodenticide . In 1979, Conrad et?al. reacted p-nitrobenzene ketone with 4-hydroxycoumarin to obtain vinegar coumarin, which is basically the same as warfarin in anticoagulant, but its metabolites also have anticoagulant effect, so the duration of anticoagulation is longer than warfarin.

Indications

Intravascular thromboembolic diseases include postoperative or postoperative thrombotic phlebitis, pulmonary embolism, myocardial infarction, and atrial fibrillation caused by embolism.

Biochem/physiol Actions

Prototype of the 4-hydroxycoumarin class of anticoagulants, which act as vitamin K antagonists, preventing formation of prothrombin. There are many reports that dicumarol also inhibits NADPH:quinone oxidoreductase (NQO(1)). In one, it inhibited NQO(1) in a pancreatic cancer cell line, causing increased formation of superoxide and inhibiting cell growth.

Pharmacology

Dicoumarin is an oral anticoagulant drug and is invalid in?vitro . Dicoumarin is a coumarin derivative, and its common mechanism is to inhibit synthesis of the coagulation factor in the liver. The structure of dicoumarin is similar to that of vitamin K and is an antagonist or a competitive inhibitor of vitamin K.?It binds to the vitamin K epoxide reductase in the liver, inhibits the conversion of vitamin K from epoxide to hydroquinone, and inhibits the recycling of vitamin K, resulting in that the glutamate side chain of vitamin K-dependent coagulation factors II, VII, IX, and X cannot be carboxylated by γ-carboxy glutamate groups, affecting the binding of coagulation factor with calcium ion, and thereby inhibiting coagulation, reducing platelet adhesion, and prolonging thrombosis time . Dicoumarol drugs have no direct confrontation with synthesized prothrombin and coagulation factor, so it is ineffective in?vitro. After withdrawal of dicoumarin, prothrombin and coagulation factors II, IV, IX, and X gradually restore to a certain level, and hence the anticoagulant effect disappear, so its efficacy can be maintained for a long time .

Pharmacokinetics

Dicoumarol is not completely absorbed in the gastrointestinal tract, often is associated with gastrointestinal discomfort, and is very rarely used clinically. Today, the only coumarin used in the United States is warfarin, but phenprocoumon and acenocomumarol are used in Europe.

Clinical Use

Dicumarol is used alone or as an adjunct to heparin in theprophylaxis and treatment of intravascular clotting. It is usedin postoperative thrombophlebitis, pulmonary embolus, acuteembolic and thrombotic occlusion of peripheral arteries, andrecurrent idiopathic thrombophlebitis. It has no effect on analready-formed embolus but may prevent further intravascularclotting. Because the outcome of acute coronary thrombosisdepends largely on extension of the clot and formation ofmural thrombi in the heart chambers, with subsequent embolization,dicumarol has been used in this condition. It hasalso been administered to arrest impending gangrene afterfrostbite. The dose, after determination of the prothrombinclotting time, is 25 to 200 mg, depending on the size and thecondition of the patient. The drug is given orally in the formof capsules or tablets. On the second day and thereafter, itmay be given in amounts sufficient to maintain the prothrombinclotting time at about 30 seconds. If hemorrhages shouldoccur, a dosage of 50 to 100 mg of menadione sodium bisulfiteis injected, supplemented by a blood transfusion.

Side effects

The most serious adverse reaction of warfarin is bleeding, which can be against by vitamin K, and if necessary, fresh plasma or whole blood can be injected into the body to confront bleeding .

Synthesis

Dicoumarol, 3,3′-methylene-bis(4-hydroxycoumarin) (24.1.8), is synthesized from 4-hydroxycoumarine (24.1.7), which is in turn synthesized from salicylic acid methyl ester by cyclization to a chromone derivative using sodium or sodium methoxide; or from o-oxyacetophenone by reacting it with diethylcarbonate in the presence of sodium ethoxide. Condensation of the resulting 4-hydroxycoumarin with formaldehyde as a phenol component gives dicoumarol.

InChI:InChI=1/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

Upstream product

• 108-31-6 maleic anhydride 
• 74803-53-5 3-(NN-dimethylaminomethyl)-4-hydroxycoumarin 
• 67-56-1 methanol 
• 1076-38-6 4-hydroxy[1]benzopyran-2-one 
• 50-00-0 formaldehyd 
• 67-68-5 dimethyl sulfoxide 
• 83272-63-3 4-hydroxy-3-pyrrolidinomethylcoumarin 
• 7732-18-5 water 
• 15059-36-6 4-acetoxycoumarin 
• 121-69-7 N,N-dimethyl-aniline 
• 579-72-6 2-(dimethylamino)benzaldehyde 
• 118157-98-5 3-methylidene-2H-chromene-2,4(3H)-dione 
• 22105-09-5 4‐hydroxycoumarin 
• 100-22-1 N,N,N',N'-tetramethyl-para-phenylenediamine 

Downstream Products

• 86739-05-1 2,3-dihydro-2-<2-hydroxybenzoyl>-4H-furo<3,2-c><1>benzopyran-4-one 
• 190248-08-9 (R)-Methoxy-phenyl-acetic acid 2-{(1R,2R)-2-[2-((R)-2-methoxy-2-phenyl-acetoxy)-phenyl]-cyclopentyl}-phenyl ester 
• 190248-06-7 C₁₉H₂₂O₂ 
• 190248-05-6 1,5-bis-(2-methoxy-phenyl)-pentane-1,5-dione 
• 63359-17-1 1.2-Di-(2'-methoxyphenyl)-Δ¹-cyclopenten 
• 4945-79-3 1,5-bis(2-hydroxyphenyl)-1,5-pentanedione 
• 86739-06-2 2-<2-hydroxybenzoyl>-4H-furo<3,2-c><1>benzopyran-4-one 
• 15074-17-6 4-hydroxy-3-methyl-2H-chromen-2-one 
• 4812-86-6 4-(phenylamino)-2H-chromen-2-one 
• 5100-81-2 6H-<1>Benzopyrano<4,3-b>chinolin-6-on 

Relevant academic research and scientific papers

Synthesis, characterization, in vitro antimicrobial and anticancer evaluation of random copolyesters bearing biscoumarin units in the main chains

A series of aliphatic-aromatic random copolyesters bearing a biscoumarin group were synthesized by phase-transfer-catalyzed interfacial polycondensation of 3,3′-methylene-bis(4-hydroxycoumarin)1 and aromatic diols such as hydroquinone, resorcinol, ethyl resorcinol, bisphenol-A, and curcumin with sebacoyl chloride. These copolyesters were obtained with yields in the range between 76 and 85 % and the inherent viscosity between 0.22 and 0.33 dl/g. All the copolyesters were found to be soluble in chlorinated and polar aprotic solvents. The chemical structures of the copolyesters were analyzed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The physical properties of copolyesters obtained by altering the aromatic diols 3, were characterized by thermogravimetric analysis, differential scanning calorimetry, gel permeation chromatography, and X-ray diffraction (XRD) technique. Copolyesters exhibited good thermal stability having a decomposition temperature above 223 °C. Copolyesters with the bisphenol group as backbone exhibited higher thermal stability than others. Results revealed that the copolyesters exhibit a glass transition temperature in the range of -11 to 54 °C. It was found that copolyester with ethyl resorcinol and curcumin shown low and high T g values, respectively. XRD measurement revealed the amorphous nature of copolyester with a low degree of crystallinity. Agar disc diffusion method was employed to study the antimicrobial activity of these random copolyesters. The synthesized copolyester was subjected to in vitro anticancer activity against lung cancer (Hep-2) cell line.

Et2AlCl promoted coupling reactions of 4-hydroxy-2-pyrone or 4- hydroxycoumarine with aldehydes: Synthesis of methylenebis(4-hydroxy-2- pyrone) or methylenebis(4-hydroxycoumarine) derivatives

Methylenebis(4-hydroxy-2-pyrone) or methylenebis(4-hydroxy-coumarine) derivatives (5) have been synthesized from 4-hydroxy-2-pyrones (6) and (8) or 4-hydroxycoumarine (10) with aldehydes (4) in the presence of diethylaluminum chloride.

Electrochemically induced cross-dehydrogenative coupling (CDC) reaction. An efficient electrochemical method for the synthesis of dicoumarols

Electrochemical synthesis of dicoumarols as anticoagulant drugs was carried out by the electrochemical oxidation of N,N,N′,N′-tetramethyl-1,4-phenylenediamine in the presence of 4-hydroxycoumarin derivatives. Electrochemically generated radical cation par

Fluorescence solvatochromism and modulated anticholinergic activity of novel coumarin compounds sequestered in human serum albumin nanocavities

A coumarin compound, 3,3′-methylenebis(4-hydroxy-2H-chromen-2-one) (MHC), and its substituted derivative, 3,3′-(phenylmethylene)bis(4-hydroxy-2H-chromen-2-one) (MHCB), possess potent anticholinergic activities, which were found to be reduced significantly in the presence of human serum albumin (HSA). The molecular interactions responsible for sequestering MHC and MHCB were explored by steady-state and time-resolved fluorescence using the modulated solvatochromic behavior of the probes as a fluorescent marker. A quantitative description of the different solvent parameters responsible for the notable solvent-dependent photo-physical properties of the investigated systems was extracted from multiple linear regression analysis of the experimental data using the Kamlet-Taft and Catalán formalisms. A series of complimentary studies involving circular dichroism measurement and molecular docking calculations revealed that the binding of both coumarin derivatives resulted in the stabilization of the α-helical structure of human serum albumin (HSA). However, significant differences in binding mechanism were noted in terms of the strength, mode and principal forces responsible for the spontaneous association of the probes into the protein-binding domain.

New biscoumarin and dihydropyran derivatives as antimicrobials

In an attempt to find a new class of antimicrobial agents, a series of biscoumarin (1-4) and dihydropyran (5 and 6) derivatives were prepared. These compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus (S. aureus ATCC 29213), methicillin-resistant S. aureus (MRSA XJ 75302), vancomycin-intermediate S. aureus (Mu50 ATCC 700699), and USA 300 (Los Angeles County clone, LAC). There are two classical intramolecular O-H···O hydrogen bonds (HBs) in the structures of biscoumarins 1-4 and the corresponding total HB energy were further performed with the density functional theory (DFT) [B3LYP/6-31G] method.

Coumarin compound as well as preparation method and application thereof

The invention provides a coumarin compound as well as a preparation method and application thereof, and mainly aims to prepare a medicine for treating cognitive impairment caused by high-fat diet and meeting partial or all standards, and weight gain caused by high-fat diet can be remarkably inhibited under the condition of not influencing physiological growth and metabolism. The compound acts on a wide range of target organs (such as intestines, livers and brains) and can remarkably relieve systemic oxidative stress induced by high-fat diet; intestinal tract and liver injuries induced by high-fat diet are blocked, lipid and glucose metabolism disorders are relieved, and insulin resistance is relieved; the brain metabolism is improved, the oxidative stress of brain tissues is relieved, and the cognitive function is improved. The compound has light toxic and side effects as a medicine, and is practicable for treating cognitive impairment caused by high-fat diet.

Redox-Triggered Switchable Synthesis of 3,4-Dihydroquinolin-2(1 H)-one Derivatives via Hydride Transfer/ N-Dealkylation/ N-Acylation

The switchable synthesis of 3-non, 3-mono, 3,3′-disubstituted 3,4-dihydroquinolin-2(1H)-ones was developed through a redox-neutral hydride-transfer/N-dealkylation/N-acylation strategy from o-aminobenzaldehyde with 4-hydroxycoumarin, and Meldrum's acid, respectively. The unprecedented strategy for the synthesis of 3,3′-highly functionalized 3,4-dihydroquinolin-2(1H)-one has been realized with the in situ utilization of the released HCHO via the o-QM involved Michael addition. In addition, the synthetic utility of this protocol has been well illustrated via concise synthesis of CYP11B2 inhibitor.

The magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs): an efficient, green and recyclable nanocatalyst for the synthesis of biscoumarin derivatives under solvent-free conditions

Abstract: The magnetic nanostructured natural hydroxyapatite (HAP/Fe3O4 NPs) as a novel magnetic nanocatalyst was synthesized and fully characterized. The excellent catalytic activity of HAP/Fe3O4 NPs was investigated in the synthesis of biscoumarin derivatives under mild, green and solvent-free conditions. A series of aromatic (bearing different functional groups), heteroaromatic and aliphatic aldehydes have been converted to biscoumarins with good to excellent isolated yields. The significant advantages offered by the present method in close agreement with green chemistry principles are: catalyst is inexpensive, non-toxic, easy handling and reusable up to six recycle runs, magnetic separation of nanostructured catalyst, simple work-up procedure, short reaction time, high yields of products and using solvent-free conditions. Graphical abstract: [Figure not available: see fulltext.].

A catalyst-free 1,4-Michael-type reaction of in situ generated ortho-quinone methides (o-QMs) with dithiocarbamic acid salts in water

Abstract: A catalyst-free conjugate addition of dithiocarbamic acid salts to in situ generated ortho-quinone methides (o-QMs) was investigated for the first time. Several dithiocarbamate derivatives of 4-hydroxycoumarine, 4-hydroxypyrone and 2-naphthol were synthesized in moderate-to-good yields in water at room temperature. Graphical abstract: [Figure not available: see fulltext.] Catalyst-free addition of dithiocarbamic acid salts to in situ generated o-QMs in water at room temperature.

Starch-sulfuric acid as a bio-supported and recyclable solid acid catalyst for rapid synthesis of α,α′-benzylidene bis(4-hydroxycoumarin) derivatives

Starch-sulfuric acid-catalyzed, simple, one pot, solvent-free, environmentally benign synthesis of α,α′-benzylidene bis(4-hydroxycoumarin) derivatives has been achieved by reaction of aromatic aldehydes with 4-hydroxycoumarin. The catalyst is reusable and has remarkable activity. This procedure has several advantages including high yields, short reaction times, easy work-up, and use of an inexpensive, moderately acidic, safe catalyst.