Physicochemical Properties
| Molecular Formula | C31H46O2 |
| Molecular Weight | 450.69574 |
| Exact Mass | 450.35 |
| CAS # | 12001-79-5 |
| Related CAS # | Vitamin K1;84-80-0 |
| PubChem CID | 5280483 |
| Appearance | Light yellow to yellow liquid（Density：0.984 g/cm3） |
| Density | 0.963g/cm3 |
| Boiling Point | 546.4ºC at 760mmHg |
| Melting Point | 112-114ºC |
| Flash Point | 200.4ºC |
| Vapour Pressure | 5.37E-12mmHg at 25°C |
| Index of Refraction | n20/D 1.527(lit.) |
| LogP | 9.157 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 2 |
| Rotatable Bond Count | 14 |
| Heavy Atom Count | 33 |
| Complexity | 696 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | [Vitamin K] |
| InChi Key | MBWXNTAXLNYFJB-LKUDQCMESA-N |
| InChi Code | InChI=1S/C31H46O2/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/h7-8,18-20,22-24H,9-17,21H2,1-6H3/b25-20+ |
| Chemical Name | 2-methyl-3-[(E)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Vitamin K acts as an essential cofactor for the enzyme γ-glutamate carboxylase (GGCX), which catalyzes the posttranslational conversion of protein-bound glutamate residues into γ-carboxyglutamate (Gla) residues in vitamin K-dependent proteins (e.g., osteocalcin, matrix Gla protein). [1] Vitamin K acts as an essential cofactor for the endoplasmic enzyme γ-glutamyl carboxylase (GGCX), which catalyzes the posttranslational conversion of glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) residues in vitamin K-dependent proteins (VKDPs). The vitamin K-dependent proteins Gas6 (growth arrest-specific gene 6 protein) and protein S are ligands for the receptor tyrosine kinases of the TAM family (Tyro3, Axl, and Mer). [3] |
| ln Vitro |
The two naturally occurring forms of vitamin K are menaquinone (vitamin K2) and phylloquinone (vitamin K1). The primary dietary supply of vitamin K is phylloquinone, which is mostly found in green leafy vegetables [1]. Menaquinone, or vitamin K2, can be found in trace levels in cheese, egg yolks, poultry, butter, and fermented soybeans. For all vitamin K-dependent proteins to be γ-glutamyl carboxylated, vitamins K1 and K2 are necessary [2]. An essential function of vitamin K is in the neurological system. Proteins Gas6 and S, which bind to TAM family receptor tyrosine kinases (Tyro3, Axl, and Mer), are bioactivated in part by vitamin K. Vitamin K plays a role in the brain's production of sphingolipids, a significant family of lipids found in high concentrations in the membranes of brain cells [3]. Vitamin K was shown to promote nerve growth factor (NGF)-mediated neurite outgrowth from PC12D cells. This action was mediated by the protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways. [3] Vitamin K (specifically phylloquinone and menaquinone-4) has survival-promoting effects on different neuronal cell types (cortex, hippocampus, and striatum) in the later stages of embryogenesis. [3] Menaquinone-4 (MK-4), and to a lesser extent phylloquinone (K1), prevented glutathione depletion-mediated oxidative injury (defined by free radical accumulation and cell death) in primary cultures of oligodendrocyte precursors and immature fetal cortical neurons. Treating cell cultures with warfarin did not affect this protective role of MK-4, indicating an action independent of VKDPs. This protective effect was shown to be mediated, at least in part, through inhibition of the enzyme 12-lipoxygenase. [3] MK-4 was shown to limit the production of interleukin-6 (IL-6) in cultured human fibroblasts and prostaglandins in cultured cells. [3] The anti-inflammatory activity of vitamin K, notably MK-4, is mediated via inhibition of the nuclear factor κB (NF-κB) signaling pathway. [3] Gas6 (a VKDP) prevents apoptosis of gonadotropin-releasing hormone (GnRH) neurons via recruitment of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway and stimulation of extracellular signal-regulated kinase (ERK) and Akt. [3] Gas6 rescues cortical neurons from amyloid β protein (Aβ)-induced apoptosis by inhibiting Ca2+ influx. [3] Gas6 promotes the survival of human oligodendrocytes in vitro and protects them from tumor necrosis factor alpha (TNFα)-induced apoptosis through activation of the Axl receptor and the PI3-K/Akt pathway. [3] In a murine microglia cell line, Gas6 treatment reduced expression of proinflammatory mediators inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) following a lipopolysaccharide (LPS) challenge. [3] Gas6 stimulates myelin synthesis by oligodendrocytes in vitro. [3] Protein S offers neuronal protection during ischemic/hypoxic injury in cultured neurons and protects neurons from NMDA-induced toxicity and apoptosis through the Tyro3-PI3-K-Akt pathway. [3] |
| ln Vivo |
The ability of vitamin K to coagulate blood is well established. Vitamin K supplementation has been shown in numerous human trials to have positive effects on insulin sensitivity and glucose tolerance, as well as to prevent insulin resistance and lower the incidence of type 2 diabetes [1]. For women, 90 μg per day and for men, 120 μg per day is the recommended appropriate intake of vitamin K [2]. A lower level of biological activity protein called carboxylated osteocalcin is elevated in cases of vitamin K insufficiency. Low dietary vitamin K consumption has been linked to lower bone mineral density or more fractures, according to numerous research. Furthermore, it has been demonstrated that vitamin K administration enhances bone turnover and lessens the deficit of carboxylated osteocalcin [4]. 1. Phylloquinone (Vitamin K1) in Humans: In a study of older men and postmenopausal women (n=355, 60-80 y), supplementation with phylloquinone (500 µg/day for 36 months) resulted in a significantly lower homeostasis model assessment of insulin resistance (HOMA-IR) among men, and a beneficial effect on fasting plasma glucose levels in the older male population, compared to the control group. No significant effects were observed in the female population. [1] 2. Phylloquinone (Vitamin K1) in Humans: In a study of prediabetic premenopausal women (aged 22-45 y), supplementation with vitamin K1 (1000 µg/day for 4 weeks) caused a significant decrease in fasting glucose, 2-hour post-oral glucose tolerance test (OGTT) glucose and insulin concentrations, and an increase in the insulin sensitivity index, compared to placebo. However, it did not affect HOMA-IR. [1] 3. Menaquinone (Vitamin K2) in Humans: In a study of healthy young men (n=18, aged ~25.5-31.5 y), supplementation with menaquinone (30 mg/day for 4 weeks) significantly increased the insulin sensitivity index and disposition index compared to placebo. [1] 4. Phylloquinone (Vitamin K1) in Animal Model: In streptozotocin (STZ)-induced diabetic Wistar rats, subcutaneous administration of phylloquinone (5 mg/kg body weight, twice a week) reduced cataract formation, potentially by regulating blood glucose homeostasis and minimizing oxidative and osmotic stress. [1] 5. Menaquinone (Vitamin K2) in Animal Model: In STZ-induced diabetic male Sprague-Dawley rats, oral administration of menatrenone (a form of vitamin K2, 30 mg/kg body weight, five times a week for 12 weeks) prevented the development of hyperglycemia. [1] 6. Menaquinone (Vitamin K2) in Animal Model: In ovariectomized rats (both exercised and non-exercised), supplementation with menaquinone-7 (0.0009 mg/kg body weight/day for 9 weeks) decreased glucose levels and increased insulin, lipocalcin-2, and adiponectin levels compared to only ovariectomized rats. [1] 7. Epidemiological Studies: Higher dietary intake of both phylloquinone and menaquinone was associated with a reduced risk of developing type 2 diabetes in several large cohort studies. For example, in a Dutch cohort, the highest versus lowest quartile of phylloquinone intake had a hazard ratio of 0.81 for type 2 diabetes. Each 10-µg increment in menaquinone intake was associated with a hazard ratio of 0.93. [1] 8. Adipokine Modulation: A 1-year follow-up study within the PREDIMED trial showed that elderly subjects who increased their dietary phylloquinone intake had significant reductions in inflammatory cytokines (leptin, TNF-α, IL-6) and other metabolic risk markers compared to those who decreased or did not change intake. [1] Administration of a vitamin K-deficient diet or warfarin treatment in rats was associated with hypoactivity (25% lower locomotor activity) and a shift from more to less exploratory behavior, but did not alter cognitive abilities assessed with a radial arm maze. [3] Lifetime consumption of a low-phylloquinone diet (80 µg kg⁻¹ diet since weaning) resulted in cognitive deficits in 20-month-old rats. These rats acquired spatial learning more slowly (longer latencies) in the Morris water maze test compared to rats fed adequate (500 µg kg⁻¹) or high (2000 µg kg⁻¹) phylloquinone diets. Motor activity, exploratory behavior, and anxiety were not affected by diet. This cognitive impairment was associated with higher concentrations of ceramides in the hippocampus and lower gangliosides in the pons medulla and midbrain. No impact was observed in rats aged 6 and 12 months. [3] In a murine in vivo model of stroke, protein S treatment significantly reduced brain infarction and edema volumes, improved post-ischemic cerebral blood flow, reduced fibrin deposition and neutrophil infiltration, and resulted in fewer apoptotic neurons and improved motor performance. [3] MK-4 was shown to limit inflammation in animal models of encephalomyelitis. [3] Phylloquinone suppressed lipopolysaccharide-induced inflammation in rats. [3] In cuprizone-treated C57B16 mice, direct administration of Gas6 into the brain increased maturation of oligodendrocyte progenitor cells and enhanced remyelination. [3] In knockout mice (Gas6⁻/⁻), the absence of Gas6 signaling was associated with decreased oligodendrocyte survival, greater cell loss, reduced overall myelination, and a delay in remyelination after cuprizone-induced demyelination. [3] Fetal exposure to warfarin derivatives during the first trimester of pregnancy results in central nervous system anomalies (warfarin embryopathy), including dilatation of cerebral ventricles, microcephaly, mental retardation, optic atrophy, and blindness. [3] In an analysis of patients in the early stages of Alzheimer's disease (AD), mean phylloquinone intakes were significantly lower (63 ± 90 µg day⁻¹) compared to cognitively intact controls (139 ± 233 µg day⁻¹), even after adjusting for energy intake. Lower consumption of green vegetables (the main vitamin K source) explained the lower intakes in AD patients. [3] In a study of 100 women with AD and 100 controls, plasma phylloquinone levels were significantly lower in AD patients and correlated positively with cognitive abilities (assessed by mini-mental state examination) and negatively with undercarboxylated osteocalcin (a marker of low vitamin K status). [3] |
| Animal Protocol |
1. STZ-induced Diabetic Wistar Rat Model (Vitamin K1): Streptozotocin (STZ)-induced diabetic Wistar rats were treated with phylloquinone via subcutaneous injection at a dose of 5 mg per kg body weight, administered twice a week. The treatment was evaluated for its effects on cataract formation and glucose homeostasis. [1] 2. STZ-induced Diabetic Sprague-Dawley Rat Model (Vitamin K2): Streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats were treated with menatrenone (a form of vitamin K2) via oral gavage at a dose of 30 mg per kg body weight, administered five times per week for a duration of 12 weeks. The effect on hyperglycemia and bone mass was assessed. [1] 3. Ovariectomized Rat Model (Vitamin K2): Ovariectomized rats (both subjected to exercise and sedentary) were supplemented with menaquinone-7 at a dose of 0.0009 mg per kg body weight per day for 9 weeks. The impact on glucose homeostasis, insulin, lipocalin-2, and adiponectin levels was examined. [1] Rats were fed diets containing different levels of phylloquinone (Vitamin K1) from weaning: a low (L) diet containing 80 µg kg⁻¹ diet, an adequate (A) diet containing 500 µg kg⁻¹ diet, and a high (H) diet containing 2000 µg kg⁻¹ diet. The animals were maintained on these diets for extended periods, up to 20 months of age. Behavioral and cognitive tests (Morris water maze, open field test, elevated plus maze) were performed at various ages (e.g., 6, 12, 20 months) to assess spatial learning, motor activity, exploratory behavior, and anxiety. Brain tissues were subsequently analyzed for sphingolipid concentrations. [3] In a study on warfarin-induced effects, rats were administered a vitamin K-deficient diet or treated with warfarin. Their psychomotor functions were then assessed using an open field paradigm to measure locomotor and exploratory activity, and cognitive abilities were tested using a radial arm maze. [3] In a murine model of stroke, protein S was administered to mice. Brain infarction, edema volumes, cerebral blood flow, fibrin deposition, neutrophil infiltration, apoptosis, and motor performance were evaluated to assess neuroprotection. [3] In a model of cuprizone-induced demyelination in C57B16 mice, Gas6 was directly administered into the brain. The effects on oligodendrocyte progenitor cell maturation and remyelination were assessed in the weeks following treatment cessation. [3] |
| ADME/Pharmacokinetics |
The literature states that there is currently no recommended dietary allowance (RDA) for Vitamin K. Adequate Intake (AI) values have been established: for phylloquinone (vitamin K1), it is 120 µg/day for men and 90 µg/day for women based on US data. For menaquinones (vitamin K2), estimated AI values are 54 µg/day for men and 36 µg/day for women based on UK data. [1] In rats, Vitamin K in the brain occurs predominantly (>98%) as menaquinone-4 (MK-4), regardless of age. MK-4 concentrations are highest in the midbrain and pons medulla, and lowest in the cerebellum, olfactory bulb, thalamus, hippocampus, and striatum. Brain MK-4 concentrations are higher in female than in male rats, decrease with age, and increase with phylloquinone intake. [3] Phylloquinone (K1) is converted to menaquinone-4 (MK-4) in tissues, including the brain. The human UBIAD1 enzyme is responsible for this biosynthesis. [3] |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Vitamin K is naturally found in human milk. Maternal vitamin K supplementation is typically not needed to meet the 75 mcg per day recommended adequate maternal dietary intake during lactation. Maternal supplementation with 5 mg daily increases milk vitamin K levels and can improve vitamin K status in breastfed infants who also receive intramuscular vitamin K shortly after birth. Although exclusively breastfed infants are at higher risk of vitamin K deficiency bleeding (VKDB), a condition that can involve intracranial hemorrhage, sometimes leading to infant death, maternal vitamin K supplementation alone is not an adequate or safe substitute for vitamin K administered directly to the newborn after birth to prevent VKDB, especially in preterm infants. ◉ Effects in Breastfed Infants Exclusive breastfeeding and failure to give infants a dose of prophylactic vitamin K at birth resulted in the death of 3 otherwise normal, consecutive male siblings from intracranial hemorrhage. A fourth male sibling was examined at 17 days of age and found to have abnormal clotting parameters. The infant and parents were found to have no genetic conditions that could account for the abnormal clotting. Within 24 hours, the infant’s clotting profile normalized after 1 mg of vitamin K injection. According to the literature reviewed, there is no documented case of toxicity in humans or animals associated with the consumption of phylloquinone or menaquinone from food or supplements. The US Institute of Medicine has indicated the absence of known toxicity. [1] |
| References |
[1]. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review. Nutrition. 2016 Jul-Aug;32(7-8):732-9. [2]. The health benefits of vitamin K. Open Heart. 2015 Oct 6;2(1):e000300. [3]. Vitamin K, an emerging nutrient in brain function. Biofactors. 2012 Mar-Apr;38(2):151-7. [4]. Vitamin K and bone health. Proc Nutr Soc. 2003 Nov;62(4):839-43. |
| Additional Infomation |
2-methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)naphthalene-1,4-dione is a member of 1,4-naphthoquinones. Vitamin K has been reported in Glycine max, Aronia melanocarpa, and other organisms with data available. Vitamin K is the term "vitamin K" refers to a group of chemically similar fat-soluble compounds called naphthoquinones: vitamin K1 (phytonadione) is found in plants and is the primary source of vitamin K for humans through dietary consumption, vitamin K2 compounds (menaquinones) are made by bacteria in the human gut, and vitamin K3 (menadione) is a water-soluble preparation available for adults only. Vitamin K is necessary for the liver to produce the coagulation factors II, VII, IX, and X, as well as the clotting factors protein C, protein S, and protein Z; vitamin K deficiency can result in deficiencies of these coagulation factors and excess bleeding. An injection of vitamin K is routinely given to newborn infants to prevent vitamin K deficiency bleeding, also known as hemorrhagic disease of the newborn. Vitamin K deficiency is rare in adults but may result from chronic malnutrition or an inability to absorb dietary vitamins. Phylloquinone is a metabolite found in or produced by Saccharomyces cerevisiae. A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: VITAMIN K 1 (phytomenadione) derived from plants, VITAMIN K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, VITAMIN K 3 (menadione). Vitamin K 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin K. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin K. See also: Phytonadione (annotation moved to). Vitamin K is a fat-soluble vitamin existing in two main natural forms: phylloquinone (vitamin K1, found in green leafy vegetables and some oils) and menaquinone (vitamin K2, found in meat, fermented foods, and produced by gut bacteria). [1] This review proposes that the beneficial effects of Vitamin K on insulin sensitivity and glucose metabolism may be mediated through several mechanisms: 1) Carboxylation of vitamin K-dependent proteins, particularly osteocalcin (OC), which is implicated in β-cell function and insulin sensitivity. 2) Regulation of circulating adipokine levels (e.g., reducing inflammatory cytokines like IL-6, TNF-α). 3) Anti-inflammatory properties, potentially via inhibition of NF-κB activation. 4) Lipid-lowering effects (e.g., reducing total cholesterol and triglycerides in animal models). [1] The literature suggests that menaquinones (vitamin K2) might be more effective than phylloquinone (vitamin K1) in activating extrahepatic vitamin K-dependent proteins and, consequently, in reducing the risk of type 2 diabetes. [1] Vitamin K is well-established for its crucial role in blood coagulation. [1] Vitamin K is a fat-soluble vitamin. Phylloquinone (Vitamin K1) is synthesized in plants and is the main dietary source. Menaquinones (Vitamin K2, MK-n) are of bacterial origin; MK-4 is synthesized from K1 in tissues. [3] Vitamin K is essential for the biological activation (γ-carboxylation) of vitamin K-dependent proteins (VKDPs) like Gas6 and protein S, which are ligands for TAM family receptor tyrosine kinases (Tyro3, Axl, Mer). [3] Vitamin K plays a crucial role in sphingolipid metabolism in the brain. Warfarin treatment decreases brain sulfatides, sphingomyelin, and cerebrosides, and reduces sulfotransferase activity. These changes can be reversed by vitamin K administration. Vitamin K intake can modulate sulfatide and ganglioside concentrations in specific brain regions. Altered sphingolipid profiles (e.g., high ceramides in hippocampus) are associated with cognitive impairment in aging animals with low vitamin K intake. [3] Vitamin K, particularly MK-4, has protective roles against oxidative stress and inflammation, potentially through mechanisms independent of VKDP carboxylation, such as inhibition of 12-lipoxygenase and NF-κB signaling. [3] Lower vitamin K intake and status are associated with Alzheimer's disease (AD). The ApoE4 genotype (a risk factor for AD) is also associated with lower circulating phylloquinone concentrations, suggesting a potential link between chronically low vitamin K and AD risk. [3] Vitamin K status may influence behavior and cognition. Deficiency is linked to psychomotor abnormalities in animals and cognitive deficits in aged animals. In humans, low intake is observed in early AD. [3] |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (Infinity mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2188 mL | 11.0939 mL | 22.1877 mL | |
| 5 mM | 0.4438 mL | 2.2188 mL | 4.4375 mL | |
| 10 mM | 0.2219 mL | 1.1094 mL | 2.2188 mL |