863-61-6

Basic information

• Product Name: Menatetrenone
• Synonyms: MENATETRENONE;MENAQUINONE 4;MENAQUINONE;1,4-naphthoquinone,2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen;2-methyl-3-(3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenyl)-1,4-naphthoqu;2-methyl-3-trans-tetraprenyl-1,4-naphthoquinone;e3100;k2(sub20)
• CAS NO: 863-61-6
• Molecular Formula: C₃₁H₄₀O₂
• Molecular Weight: 444.65
• Product Categories: Vitamins and derivatives;Osteoporosis;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics
• Mol File: 863-61-6.mol
• Article Data: 8

Chemical Properties

• Melting Point: 350C
• Boiling Point: 494.59°C (rough estimate)
• Flash Point: 2℃
• Appearance: yellow crystals
• Density: 1.0461 (rough estimate)
• Vapor Pressure: 4.97E-13mmHg at 25°C
• Refractive Index: 1.5045 (estimate)
• Storage Temp.: −20°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly, Heated)
• CAS DataBase Reference: Menatetrenone(CAS DataBase Reference)
• NIST Chemistry Reference: Menatetrenone(863-61-6)
• EPA Substance Registry System: Menatetrenone(863-61-6)

Safety Data

• Safety Statements: 22-24/25
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 3
• RTECS: QL9279500
• Hazardous Substances Data: 863-61-6(Hazardous Substances Data)

Usage

Description

Menatetrenone (also known as MK-4) is a manaquinone compound and a vitamin K compound which can be used as a hemostatic agent as well as adjunctive therapy for the pain of osteoporosis. It mainly takes effects through modulating the signaling of certain tyrosine kinases, thereby affecting several transcription factors including c-myc and c-fos. It is capable of inhibiting tumor cells growth through inducing apoptosis and cell cycle arrest. It can be produced via the conversion of vitamin K1 inside the body including the testes, pancreas and arterial walls.

References

https://pubchem.ncbi.nlm.nih.gov/compound/menatetrenone#section=Biomolecular-Interactions-and-Pathways https://en.wikipedia.org/wiki/Menatetrenone

Chemical Properties

Yellow Crystals

Uses

Different sources of media describe the Uses of 863-61-6 differently. You can refer to the following data:
1. Menaquinones are isoprenoid quinones of the naphthalene series and belongs to the K2 Vitamin homologs. Menaquinones were originally discovered as the anti-hemorrhagic factor and now encompasses a vari ety of physiological processes. Menaquinone 4 has four isoprene residue in its side chain and is also commonly refered to as menatetrenone. Menaquinone-4 is the most common type of vitamin K2 and is k nown as a hemostatic agent and is used as adjunctive therapy for the pain of osteoporosis.
2. Menaquinones are isoprenoid quinones of the naphthalene series and belongs to the K2 Vitamin homologs. Menaquinones were originally discovered as the anti-hemorrhagic factor and now encompasses a variety of physiological processes. Menaquinone 4 has four isoprene residue in its side chain and is also commonly refered to as menatetrenone. Menaquinone-4 is the most common type of vitamin K2 and is known as a hemostatic agent and is used as adjunctive therapy for the pain of osteoporosis.

Definition

ChEBI: A menaquinone whose side-chain contains 4 isoprene units in an all-trans-configuration.

General Description

Menaquinone (K2), a vitamin K2 homologue with four isoprene units. It has been reported to enhance bone formation and plays a vital role in the production of blood coagulation factors.

Biochem/physiol Actions

Menatetrenone (MK-4) is one of nine forms of vitamin K2 which is ubiquitously present in extrahepatic tissues. MK-4 has a number of metabolic and anti-neoplastic activities.

InChI:InChI=1/C31H40O2/c1-22(2)12-9-13-23(3)14-10-15-24(4)16-11-17-25(5)20-21-27-26(6)30(32)28-18-7-8-19-29(28)31(27)33/h7-8,12,14,16,18-20H,9-11,13,15,17,21H2,1-6H3/b23-14+,24-16+,25-20+

Synthetic route

(2'E,6'E,10'E,14'E)-2-(3',7',11',15'-tetramethylhexadeca-2',6',10',14'-tetraenyl)-1,4-dimethoxy-3-methylnaphthalene (66958-54-1) → menatetrenone (863-61-6)

Conditions	Yield
With ammonium cerium (IV) nitrate In water; acetonitrile at 10 - 20℃; for 1h;	90.6%
With ammonium cerium(IV) nitrate; triisooctyl amine In hexane; water; acetonitrile for 0.5h;	86%
With ammonium cerium(IV) nitrate In dichloromethane; acetonitrile at 0℃; for 0.5h;	72%

2-<9'-(2-pyridylthio)-tetraprenyl>-3-methyl-1,4-dimethoxynaphthalene (94827-99-3) → menatetrenone (863-61-6) + 2-Methyl-3-((2E,6E,9E)-3,7,11,15-tetramethyl-hexadeca-2,6,9,14-tetraenyl)-2,3-dihydro-[1,4]naphthoquinone

Conditions	Yield
With lithium aluminium tetrahydride; ammonium cerium(IV) nitrate; lithium methanolate; copper dichloride 1.) THF, 1 h, reflux; 2.) CH2Cl2, CH3CN, H2O, 0 deg C; Yield given. Multistep reaction. Yields of byproduct given;

2-(5'-p-tosyl-tetraprenyl)-3-methyl-1,4-dibenzyloxynaphthalene (94828-03-2) → menatetrenone (863-61-6) + 2-Methyl-3-((2E,5E,10E)-3,7,11,15-tetramethyl-hexadeca-2,5,10,14-tetraenyl)-[1,4]naphthoquinone

Conditions	Yield
With oxygen; lithium; ethylamine 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O; Yield given. Multistep reaction;

2-(9'-p-tosyl-tetraprenyl)-3-methyl-1,4-dibenzyloxynaphthalene (94828-02-1) → menatetrenone (863-61-6) + 2-Methyl-3-((2E,6E,9E)-3,7,11,15-tetramethyl-hexadeca-2,6,9,14-tetraenyl)-2,3-dihydro-[1,4]naphthoquinone

Conditions	Yield
With oxygen; lithium; ethylamine 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O; Yield given. Multistep reaction;

4-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-04-8) → menatetrenone (863-61-6)

Conditions	Yield
With isotonic phosphate buffer; rat liver homogenate at 37℃; pH=7.4; Kinetics; Further Variations:; Reagents; Hydrolysis;

1-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-03-7) → menatetrenone (863-61-6)

Conditions	Yield
With isotonic phosphate buffer; rat liver homogenate at 37℃; pH=7.4; Kinetics; Further Variations:; Reagents; Hydrolysis;

1,4-bis(N,N-dimethylglycyloxy)-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-05-9) → menatetrenone (863-61-6) + 4-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-04-8) + 1-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-03-7)

Conditions	Yield
With isotonic phosphate buffer; rat liver homogenate at 37℃; pH=7.4; Kinetics; Further Variations:; Reagents; Hydrolysis;

1-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene hydrocloride → menatetrenone (863-61-6)

Conditions	Yield
With male Wistar rat liver microsome preparation In water at 25℃; Enzyme kinetics; Hydrolysis; Enzymatic reaction;

4-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene hydrochloride → menatetrenone (863-61-6)

Conditions	Yield
With male Wistar rat liver microsome preparation In water at 25℃; Enzyme kinetics; Hydrolysis; Enzymatic reaction;

1,4-bis(N,N-dimethylglycyloxy)-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene dihydrochloride → menatetrenone (863-61-6)

Conditions	Yield
With male Wistar rat liver microsome preparation In water at 25℃; Enzyme kinetics; Hydrolysis; Enzymatic reaction;

2-methyl-1,4-naphthohydroquinone (481-85-6) + 3,7,11,15-tetramethyl-hexadec-1,6t,10t,14-tetraen-3-ol → menatetrenone (863-61-6)

Conditions	Yield
With boron trifluoride diethyl etherate; zinc(II) chloride anschliessendes Behandeln mit Ag2O;

farnesyl bromide (24163-93-7, 24163-94-8, 56881-57-3, 6874-67-5, 28290-41-7) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / t-BuOK / tetrahydrofuran / 5 h / -20 °C 2: 95 percent / Pd(dppe)Cl2; LiEt3BH / tetrahydrofuran / 1 h / 0 °C 3: 72 percent / aq. CAN / CH2Cl2; acetonitrile / 0.5 h / 0 °C View Scheme

(2′E)-2-(3′-methyl-4′-phenylsulfonylbut-2′-enyl)-1,4-dimethoxy-3-methylnaphthalene (73875-18-0) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / t-BuOK / tetrahydrofuran / 5 h / -20 °C 2: 95 percent / Pd(dppe)Cl2; LiEt3BH / tetrahydrofuran / 1 h / 0 °C 3: 72 percent / aq. CAN / CH2Cl2; acetonitrile / 0.5 h / 0 °C View Scheme

(2'E,6'E,10'E,14'E)-2-(4'-phenylsulfonyl-3',7',11',15'-tetramethylhexadeca-2',6',10',14'-tetraenyl)-1,4-dimethoxy-3-methylnaphthalene (618457-08-2) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / Pd(dppe)Cl2; LiEt3BH / tetrahydrofuran / 1 h / 0 °C 2: 72 percent / aq. CAN / CH2Cl2; acetonitrile / 0.5 h / 0 °C View Scheme

2-bromo-3-methyl-1,4-dimethoxynaphthalene (53772-33-1) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 58 percent / n-BuLi / diethyl ether / 1.) 0 deg , 10 min; 1 h, 2.) 0 deg C, 30 min 2: 2.) THF, 0-5 deg C, 10 min, sonication 3: 86 percent / cerium ammonium nitrate, Adogen / acetonitrile; H2O; hexane / 0.5 h View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C / Inert atmosphere 2.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 15 h / 70 °C 3.1: ammonium cerium (IV) nitrate / acetonitrile; water / 1 h / 10 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 10 h / 100 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 100 °C 3: ammonium cerium (IV) nitrate / acetonitrile; water / 1 h / 10 - 20 °C View Scheme

(2Ξ,6E,10E)-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenal (132513-59-8) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 58 percent / n-BuLi / diethyl ether / 1.) 0 deg , 10 min; 1 h, 2.) 0 deg C, 30 min 2: 2.) THF, 0-5 deg C, 10 min, sonication 3: 86 percent / cerium ammonium nitrate, Adogen / acetonitrile; H2O; hexane / 0.5 h View Scheme

(2'E,6'E,10'E)-2-Methyl-3-(1'-hydroxy-3',7',11',15'-tetramethyl-2',6',10',14'-hexadecatetraenyl)-1,4-dimethoxynaphthalene (156840-09-4) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.) THF, 0-5 deg C, 10 min, sonication 2: 86 percent / cerium ammonium nitrate, Adogen / acetonitrile; H2O; hexane / 0.5 h View Scheme

trans-geranyl bromide (6138-90-5) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / dimethylformamide / 16 h / Ambient temperature 2: 75 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 3: 1.) CuCl2, LiAlH4, MeOLi; 2.) ceric ammonium nitrate / 1.) THF, 1 h, reflux; 2.) CH2Cl2, CH3CN, H2O, 0 deg C View Scheme

3,7-dimethyl-1-(p-toluenesulfonyl)-2(E),6-octadiene (53254-60-7) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

(2E,6E)-3,7,11-trimethyl-1-(p-tolylsulfonyl)dodeca-2,6,10-triene (68690-45-9, 80370-68-9, 53254-63-0) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

2-[(2E)-3,7-dimethyl-2,6-octadienyl]sulfanylpyridine (82895-40-7) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) CuCl2, LiAlH4, MeOLi; 2.) ceric ammonium nitrate / 1.) THF, 1 h, reflux; 2.) CH2Cl2, CH3CN, H2O, 0 deg C View Scheme

2-(8-bromo-3,7-dimethyl-octa-2,6-dienyl)-1,4-dimethoxy-3-methyl-naphtalene (94828-13-4) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) CuCl2, LiAlH4, MeOLi; 2.) ceric ammonium nitrate / 1.) THF, 1 h, reflux; 2.) CH2Cl2, CH3CN, H2O, 0 deg C View Scheme

8-(1,4-dimethoxy-3-methyl-naphtalen-2-yl)-2,6-dimethyl-octa-2,6-dien-1-ol (94828-05-4) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: PBr3 / diethyl ether / 1.5 h / 0 °C 2: 75 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 3: 1.) CuCl2, LiAlH4, MeOLi; 2.) ceric ammonium nitrate / 1.) THF, 1 h, reflux; 2.) CH2Cl2, CH3CN, H2O, 0 deg C View Scheme

(E)-4-(1,4-Bis-benzyloxy-3-methyl-naphthalen-2-yl)-2-methyl-but-2-en-1-ol (94828-30-5) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: PBr3 / diethyl ether / 1.5 h / 0 °C 2: 87 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 3: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

1,4-Bis-benzyloxy-2-((E)-4-bromo-3-methyl-but-2-enyl)-3-methyl-naphthalene (94828-04-3) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

(2E,6E)-8-(1,4-Bis-benzyloxy-3-methyl-naphthalen-2-yl)-2,6-dimethyl-octa-2,6-dien-1-ol (94828-06-5) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: PBr3 / diethyl ether / 1.5 h / 0 °C 2: 86 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 3: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

1,4-Bis-benzyloxy-2-((2E,6E)-8-bromo-3,7-dimethyl-octa-2,6-dienyl)-3-methyl-naphthalene (94828-14-5) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / 1.) hexamethylphosphoric triamide, BuLi / tetrahydrofuran; hexane / -70 - 0 °C 2: 1.) Li in EtNH2; 2.) oxygen / 1.) THF, -70 deg C; 2.) THF, MeOH, H2O, Et2O View Scheme

menahydroquinone-4 (39776-45-9) → menatetrenone (863-61-6)

Conditions	Yield
With oxygen; sodium chloride In hexane; water; ethyl acetate; toluene at 25 - 40℃; for 3h; Product distribution / selectivity;
With oxygen In water; toluene at 30 - 60℃; for 15h; Product distribution / selectivity;

1,4-dimethoxy-2-methylnaphthalene (53772-19-3) → menatetrenone (863-61-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: bromine / dichloromethane / 2 h / 10 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 15 h / 70 °C 4.1: ammonium cerium (IV) nitrate / acetonitrile; water / 1 h / 10 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: bromine / dichloromethane / 2 h / 10 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 10 h / 100 °C 3: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 100 °C 4: ammonium cerium (IV) nitrate / acetonitrile; water / 1 h / 10 - 20 °C View Scheme

menatetrenone (863-61-6) → menahydroquinone-4 (39776-45-9)

Conditions	Yield
With sodium tetrahydroborate In methanol; di-isopropyl ether for 0.166667h; Reduction;

menatetrenone (863-61-6) → C31H40O2

Conditions	Yield
In acetonitrile at 20 - 22℃; Flash photolysis;

menatetrenone (863-61-6) → 4-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-04-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4 / diisopropyl ether; methanol / 0.17 h 2: dicyclohexylcarbodiimide; pyridine / 24 h / 20 °C View Scheme

menatetrenone (863-61-6) → 1-N,N-dimethylglycyloxy-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-03-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4 / diisopropyl ether; methanol / 0.17 h 2: dicyclohexylcarbodiimide; pyridine / 24 h / 20 °C View Scheme

menatetrenone (863-61-6) → 1,4-bis(N,N-dimethylglycyloxy)-2-methyl-3-tetraprenyl-4-hydroxy-naphthalene (197071-05-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaBH4 / diisopropyl ether; methanol / 0.17 h 2: dicyclohexylcarbodiimide; pyridine / 24 h / 20 °C View Scheme

Upstream product

• 481-85-6 2-methyl-1,4-naphthohydroquinone 
• 1117-51-7 (5Z,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one 
• 3953-35-3 (5E,9Z)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one 
• 3879-26-3 (Z)-nerylacetone 
• 78-70-6 3,7-dimethylocta-1,6-dien-3-ol 
• 3796-70-1 trans geranyl acetone 
• 58-27-5 menadione 
• 590401-48-2 1,4-dimethoxy-3-methyl-2-naphthylboronic acid 
• 53772-19-3 1,4-dimethoxy-2-methylnaphthalene 
• 39776-45-9 menahydroquinone-4 
• 94828-14-5 1,4-Bis-benzyloxy-2-((2E,6E)-8-bromo-3,7-dimethyl-octa-2,6-dienyl)-3-methyl-naphthalene 
• 94828-06-5 (2E,6E)-8-(1,4-Bis-benzyloxy-3-methyl-naphthalen-2-yl)-2,6-dimethyl-octa-2,6-dien-1-ol 
• 94828-04-3 1,4-Bis-benzyloxy-2-((E)-4-bromo-3-methyl-but-2-enyl)-3-methyl-naphthalene 
• 94828-30-5 (E)-4-(1,4-Bis-benzyloxy-3-methyl-naphthalen-2-yl)-2-methyl-but-2-en-1-ol 

Downstream Products

• 39776-45-9 menahydroquinone-4 

Relevant articles and documents

2Δ-Stereocontrolled Entry to (E)- or (Z)-Prenyl Aromatics and Quinones. Synthesis of Menaquinone-4

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Method for producing quinone compound

A method for producing menatetrenone that does not have a deleterious influence on the environment, that is safe even when applied to large-scale production, and that is also simple to operate, wherein a compound represented by the following formula (1) is produced by treating with an oxygen source, and without the addition of an additive other than water or aqueous sodium chloride solution, a reaction solution consisting essentially of a solution of a compound represented by the following formula (2) dissolved in a solvent:

Bioreductive activation-independent delivery of menahydroquinone-4 via prodrug and its action in warfarin-poisoned rat liver

The ester prodrugs of menahydroquinone-4 (menahydroquinone), the active form of menaquinone-4 (menaquinone, vitamin K(2(20)), were identified in previous reports as prodrugs that could achieve the systemic liver-specific delivery of menahydroquinone. The present study was undertaken to investigate the mechanism of the prodrugs for vitamin K-dependent carboxylation and their action in the warfarin-poisoned rat liver. A rat liver microsomal test system for assessing the carboxylation mechanism of the prodrugs was developed. In this system, the pathways for cleavage (hydrolysis) of the prodrug and for the reductive activation of menaquinone can be provided, and the vitamin K-dependent carboxylase can accept the synthetic tripeptide BOC-Glu-Glu-Leu-OMe as substrate. With this system, the carboxylation stimulated with the prodrugs and the enzymatic cleavage of the prodrugs were determined. The prodrug could stimulate the carboxylase activity in the absence of dithiothreitol, an artificial activator of the reductive activation pathway of menaquinone, and the activity order was as follows: 1-monoester > 1,4-bisester > 4-monoester. The carboxylation activities of the prodrugs were in the same order as the liver microsomal enzymatic reconversion characteristics of the prodrugs. The carboxylation activity of the selected prodrug (1-monoester) was strongly inhibited in the presence of eserine, a carboxylesterase inhibitor. The prodrug could also stimulate the carboxylase under warfarin-poisoning conditions, where the vitamin K cycle was strongly inhibited. The results confirmed that the prodrugs could generate menahydroquinone in the active site, and that the resultant menahydroquinone could act as cofactor for the carboxylase without reductive activation processes of menaquinone to menahydroquinone. Such bioreductive activation-independent vitamin K-dependent carboxylation characteristics of the prodrugs leads to enhanced pharmacological efficacy in the treatment of hypoprothrombinaemia induced in patients undergoing coumarin and cephalosporin therapies.