molecular formula C19H16O4 B611796 华法林 CAS No. 81-81-2

华法林

货号: B611796
CAS 编号: 81-81-2
分子量: 308.3 g/mol
InChI 键: PJVWKTKQMONHTI-UHFFFAOYSA-N
注意: 仅供研究使用。不适用于人类或兽医用途。
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生化分析

Biochemical Properties

Warfarin’s biotransformation is a complex process involving over nine different metabolites . It interacts with cytochrome P450 2C (Cyp2c) enzymes, which are instrumental in the biotransformation of Warfarin to its 7-hydroxylated metabolite .

Cellular Effects

Warfarin alters vitamin K metabolism, which has significant consequences as vitamin K-dependent (VKD) proteins function in numerous physiologies in many tissues . These proteins may be poorly carboxylated and dysfunctional if the second activity is not ubiquitously expressed similar to VKORC1 .

Molecular Mechanism

Warfarin inhibits the vitamin K oxidoreductase (VKORC1), which generates vitamin K hydroquinone (KH 2) required for the carboxylation and consequent activation of VKD proteins . Warfarin uncouples the 2 reactions that fully reduce KO .

Temporal Effects in Laboratory Settings

It is known that Warfarin’s metabolism involves a rate-limiting step in the biotransformation of Warfarin to its 7-hydroxylated metabolite .

Dosage Effects in Animal Models

It is known that Warfarin’s metabolism is a complex process involving over nine different metabolites .

Metabolic Pathways

Warfarin is involved in the metabolic pathway of vitamin K. It inhibits VKORC1, which generates KH 2 required for the carboxylation and consequent activation of VKD proteins .

Transport and Distribution

It is known that Warfarin interacts with Cyp2c enzymes during its metabolism .

Subcellular Localization

Warfarin and VKORC1 both reside in the endoplasmic reticulum and mediate VKD protein modification during secretion

准备方法

合成路线和反应条件

华法林可以通过多种方法合成。 一种常见的合成路线是将4-羟基香豆素与苄叉丙酮在碱性条件下缩合 . 反应通常使用氢氧化钠作为碱,乙醇作为溶剂。 然后通过重结晶对产物进行纯化。

工业生产方法

华法林的工业生产涉及使用与实验室环境中类似的方法进行大规模合成。 该工艺针对产量和纯度进行了优化,通常涉及连续流反应器和先进的纯化技术 . 最终产品被配制成片剂或注射液用于医疗用途。

化学反应分析

反应类型

华法林会发生各种化学反应,包括氧化、还原和取代反应 .

常用试剂和条件

主要产物

由这些反应形成的主要产物取决于所使用的具体试剂和条件。 例如,华法林的氧化会导致醌的形成,而还原会导致羟基衍生物的形成 .

属性

IUPAC Name

4-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-2-one
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InChI

InChI=1S/C19H16O4/c1-12(20)11-15(13-7-3-2-4-8-13)17-18(21)14-9-5-6-10-16(14)23-19(17)22/h2-10,15,21H,11H2,1H3
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InChI Key

PJVWKTKQMONHTI-UHFFFAOYSA-N
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Canonical SMILES

CC(=O)CC(C1=CC=CC=C1)C2=C(C3=CC=CC=C3OC2=O)O
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Molecular Formula

C19H16O4
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DSSTOX Substance ID

DTXSID5023742
Record name Warfarin
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Molecular Weight

308.3 g/mol
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Physical Description

Warfarin is an odorless and colorless solid. Used as a rodenticide for Norway rats and for house mice. (EPA, 1998), Colorless, odorless, crystalline powder. [rodenticide]; [NIOSH], Solid, COLOURLESS-TO-WHITE POWDER., Colorless, odorless, crystalline powder or solid., Colorless, odorless, crystalline powder. [Note: Rodenticide.]
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Boiling Point

Decomposes (NIOSH, 2023), decomposes, Decomposes
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Solubility

0.002 % (NIOSH, 2023), Solubility: 1 g in 1.5 mL water, 1.9 mL alcohol, >10,000 mL chloroform, >10,000 mL ether /Warfarin potassium/, In water, 17 mg/L at 20 °C, Soluble in acetone, dioxane; moderately soluble in methanol, ethanol, isopropanol, some oils; freely soluble in alkaline aqueous solution (forms a water-sol sodium salt); practically insoluble in benzene, cyclohexane, Skellysolves A and B., In acetone 65, chloroform 56, dioxane 100 (all in g/L, 20 °C), 0.017 mg/mL at 20 °C, Solubility in water, g/100ml at 20 °C: 0.0017 (very poor), 0.002%
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Density

Relative density (water = 1): 1.4
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Vapor Density

Relative vapor density (air = 1): 10.6
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Vapor Pressure

0.09 mmHg at 71 °F (NIOSH, 2023), 0.09 [mmHg], 1.5X10-3 mPa /1.125X10-8 mm Hg/ at 25 °C, Vapor pressure, Pa at 20 °C: (negligible), 0.09 mmHg at 71 °F, (71 °F): 0.09 mmHg
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Mechanism of Action

Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca2+ and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K1 by vitamin K epoxide reductase then back to vitamin KH2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K2, functionally identical to vitamin K1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K2
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Color/Form

Crystals from alcohol, White powder, The racemate forms colorless crystals

CAS No.

81-81-2
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Record name Coumarin, 3-(alpha-acetonylbenzyl)-4-hydroxy-
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Melting Point

322 °F (EPA, 1998), 161 °C, 322 °F
Record name WARFARIN
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Record name Warfarin
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Record name WARFARIN
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Record name Warfarin
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Synthesis routes and methods I

Procedure details

Control, blank, and experimental reaction mixtures were made for each experiment. Control and blank reaction mixtures were made up with vitamin K and without vitamin K, respectively. Experimental reaction mixtures contained both vitamin K and a vitamin K antagonist. The control reaction mixture contained 3.00 ml of microsomal suspension, 0.81 ml of buffer II, 1.20 ml of an ATP-generating system (final concentrations: 1 mM ATP, 10 mM phosphocreatine, 2.5 mM Mg[acetate]2 ·4H2O, 20 μg/ml creatine phosphokinase [52 U/ml]), 0.60 ml of NADH (final concentration 2 mM), 0.30 ml of dithiothreitol (final concentration 7 mM) dissolved in buffer II, 0.060 ml of NaH14CO3 (1.0 μCi/μl; added 0.5 min prior to reaction initiation), and at the time of reaction initiation 0.030 ml of vitamin K1 (final concentration 20 μg/ml) diluted in 0.85% sodium chloride solution. This vitamin K concentration is associated with maximal in vitro incorporation of added H14CO3 into vitamin K-dependent substrate proteins (J. Biol. Chem. 251, 2770-2776). The blank reaction mixture consisted of the same components except that vitamin K was replaced by an equal volume of isotonic saline. The experimental reaction mixtures were made up in the same way as the control reaction mixtures with the exceptions that: (1) a volume of buffer II was replaced by a volume of buffer II containing an inhibitor of vitamin K-dependent carboxylation, and (2) all individual volumes were two-thirds of those in the control reaction mixtures. The sodium salts of TCP, phenindione, and warfarin were formed in aqueous sodium hydroxide solution (J. Am. Chem. Soc. 83, 2676-2679) and were freely soluble in buffer II at all concentrations used in these studies. Chloro-K1 was formulated as an oil-in-water emulsion with Tween 80 (5% v/v final concentration), while chloro-K3 was formulated as a suspension in Tween 80 (5% v/v final concentration) (Molecular Pharmacology 10, 373-380).
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Quantity
0.03 mL
Type
reactant
Reaction Step Two
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Three
[Compound]
Name
( 1 )
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Four
[Compound]
Name
II
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Five
[Compound]
Name
II
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Six
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Seven
[Compound]
Name
( 2 )
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Seven
Quantity
0 (± 1) mol
Type
solvent
Reaction Step Eight
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Nine
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Ten
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Eleven
[Compound]
Name
vitamin K
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Twelve
[Compound]
Name
microsomal suspension
Quantity
3 mL
Type
reactant
Reaction Step Thirteen
[Compound]
Name
II
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Fourteen
Name
Quantity
1.2 mL
Type
reactant
Reaction Step Fifteen

Synthesis routes and methods II

Procedure details

To show that non-binding compounds do not significantly influence the FT-IR spectrum of a biological macromolecule when mixed with the biological macromolecule, 3 μg of NMT was mixed with 10 μg each of Bacitracin (trace 1), Erythromycin (2), Fusidic Acid (3) and a fungal extract (4) and a differential FT-IR spectrum of each sample was obtained (FIG. 3). The non-binding compounds did not alter the spectrum of NMT. However, a nonspecific binding compound, Warfarin (60 μg), did produce a detectable peak shift for NMT.
Quantity
10 μg
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One

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