Synthesis of 2-methyl-1,4-naphthoquinones with higher gamma-glutamyl carboxylase activity than MK-4 both in vitro and in vivo

Vermeer, Cees; Hoofd, Cynthia van 't; Knapen, Marjo H. J.; Xanthoulea, Sofia

doi:10.1016/j.bmcl.2016.11.073

Cited by 9 publications

(11 citation statements)

References 12 publications

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“…Despite traditional high cost and low yield, chemically synthetized vitamin K2 has gained renewed interest with new and optimized methods for an efficient and stereoselective production of high pure (99.9%) all-trans vitamin MK-7 with a moderate yield (11% starting from menadione) [148]. Additionally, chemical approaches have been used to synthetize novel vitamin K2 analogues, reported to have higher bioactivities when compared with their natural counterparts [136,[149][150][151]. These new compounds, with vitamin K activity but different pharmacological properties compared with the natural homologues, might reveal novel and interesting biological activities for commercialization as active diet supplements.…”

Section: Vitamin K2mentioning

confidence: 99%

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases

et al. 2020

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Vitamin K health benefits have been recently widely shown to extend beyond blood homeostasis and implicated in chronic low-grade inflammatory diseases such as cardiovascular disease, osteoarthritis, dementia, cognitive impairment, mobility disability, and frailty. Novel and more efficient nutritional and therapeutic options are urgently needed to lower the burden and the associated health care costs of these age-related diseases. Naturally occurring vitamin K comprise the phylloquinone (vitamin K1), and a series of menaquinones broadly designated as vitamin K2 that differ in source, absorption rates, tissue distribution, bioavailability, and target activity. Although vitamin K1 and K2 sources are mainly dietary, consumer preference for diet supplements is growing, especially when derived from marine resources. The aim of this review is to update the reader regarding the specific contribution and effect of each K1 and K2 vitamers in human health, identify potential methods for its sustainable and cost-efficient production, and novel natural sources of vitamin K and formulations to improve absorption and bioavailability. This new information will contribute to foster the use of vitamin K as a health-promoting supplement, which meets the increasing consumer demand. Simultaneously, relevant information on the clinical context and direct health consequences of vitamin K deficiency focusing in aging and age-related diseases will be discussed.

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Section: Vitamin K2mentioning

confidence: 99%

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases

et al. 2020

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“…This could be because their core structure, 4-hydroxycoumarin (Figure 1A), binds to the same site in VKOR. Therefore, it seemed logical that compounds with different core structures (ie, other than coumarin) may be associated with a different binding site in the target enzyme, and thus have a different mechanism of action.As a continuation to our previous work, we explored the possibility of derivatizing vitamin K as an inhibitor for VKD carboxylation.Vitamin K comprises a group of structurally similar compounds that share a 2-methyl-1,4-naphthoquinone core structure and are distinctly different from the coumarins (Figure 1A), but all differ in the side-chain at the 3-position 30,46. Lowenthal et al have shown that replacing the 2-methyl group of phylloquinone with a chlorine atom Characterization of UBIAD1-dependent VKD carboxylation of COT derived vitamin K analogue in HEK293 cells.…”

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confidence: 99%

A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase

Chen

Liu

Furukawa

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Vitamin K antagonists (VKAs), such as warfarin, have remained the cornerstone of oral anticoagulation therapy in the prevention and treatment of thromboembolism for more than half a century. They function by impairing the biosynthesis of vitamin K‐dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially the result of genetic variations of VKOR. Objectives The goal of this study was to search for an improved VKA that is tolerant to the genetic variations of its target enzyme. Methods A series of vitamin K derivatives with benzyl and related side‐chain substitutions at the 3‐position of 1,4‐naphthoquinone were synthesized. The role of these compounds in VKD carboxylation was evaluated by mammalian cell‐based assays and conventional in vitro activity assays. Results Our results showed that replacing the phytyl side‐chain with a methylene cyclooctatetraene (COT) moiety at the 3‐position of vitamin K1 converted it from a substrate to an inhibitor for VKD carboxylation. Strikingly, this COT‐vitamin K derivative displayed a similar inhibition potency in warfarin‐resistant VKOR mutations whose warfarin resistance varied more than 400‐fold. Further characterization of COT‐vitamin K for the inhibition of VKD carboxylation suggested that this compound targets multiple enzymes in the vitamin K redox cycle. Importantly, the anticoagulation effect of COT‐vitamin K can be rescued with high doses of vitamin K1. Conclusion We discovered a vitamin K analogue that functions as a VKA and is tolerant to genetic variations in the target enzyme.

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“…They demonstrated their biological activity as carboxylase agonists compounds, in particular they found that compounds 13 (C-16 tail) and 15 (C-14 tail) showed strong bioactivity while compounds 12 (C-17 tail) and 14 (C-18 tail) showed vice versa a weak activity. This finding is particularly interesting, because compared to naturally occurring forms of vitamin K, these synthetic vitamin K derivatives with higher bioactivity might be used in pharmacological interventions, rather than using traditional vitamin K supplements, in the clinical setting (20). Vitamin K1 is mainly present in the liver, heart and pancreas, while MK-4 is better represented in the kidneys, brain and pancreas.…”

Section: Metabolism and Recycling Of Vitamin Kmentioning

confidence: 97%

“…Its polymorphisms have been associated with BMD alterations (both lower and higher) (18,19). Recently, Vermeer et al (20) synthesized novel 2-methyl-1,4-naphthoquinone derivatives, differing in the side-chain at the 3-position. They demonstrated their biological activity as carboxylase agonists compounds, in particular they found that compounds 13 (C-16 tail) and 15 (C-14 tail) showed strong bioactivity while compounds 12 (C-17 tail) and 14 (C-18 tail) showed vice versa a weak activity.…”

Section: Metabolism and Recycling Of Vitamin Kmentioning

confidence: 99%

Vitamin K and bone

Fusaro

Mereu²,

Aghi

et al. 2017

ccmbm

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SummaryVitamin K is mainly known as an agent involved in blood coagulation, maintaining the activity of coagulation factors in the liver. In addition, epidemiological studies suggested that a lack of vitamin K is associated with several diseases, including osteoporosis and vascular calcification. There are two main kinds of vitamin K: Phylloquinone (or PK) and Menaquinones (MKn), both act as co-enzyme of y-glutamyl carboxylase (GGCX) transforming undercarboxylated in carboxylated vitamin K dependent proteins, such as Bone Gla Protein (or Osteocalcin) and Matrix Gla Protein. Recently, Vitamin K was also identified as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species Pregnane X Receptor: PXR), expressed in osteoblasts. The purpose of this literature review is to evaluate the protective role of Vitamin K in bone and vascular health.

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Synthesis of 2-methyl-1,4-naphthoquinones with higher gamma-glutamyl carboxylase activity than MK-4 both in vitro and in vivo

Cited by 9 publications

References 12 publications

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases

Vitamin K as a Diet Supplement with Impact in Human Health: Current Evidence in Age-Related Diseases

A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase

Vitamin K and bone

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