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

Cees Vermeer*, Cynthia van 'T Hoofd, Marjo H. J. Knapen, Sofia Xanthoulea

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)


Vitamin K is the collective term for compounds that share a 2-methyl-1,4-naphthoquinone ring, but differ in the side-chain at the 3-position. We synthesized novel 2-methyl-1,4-naphthoquinone derivatives with different side chain length at the 3-position. Derivatives with C-14 and C-16 tails showed the highest in vitro bioactivity resulting in 2.5 and 2-fold higher carboxylated osteocalcin synthesis in MG63 cells than menaquinone-4 (MK-4, form of vitamin K2). Longer side chain lengths resulted in lower bioactivity. The in vivo vitamin K activity of the C-14 tail derivative was further tested in WRY rats receiving a vitamin IC-deficient diet that resulted in a 40% decrease of prothrombin activity. The C-14 tail derivative was able to counteract the effects on vitamin K deficiency induced by the diet and resulted in the complete restoration of prothrombin activity. Compared to naturally occurring forms of vitamin K, synthetic vitamin K derivatives may have higher bioactivity and different pharmacological characteristics that are more favorable for use as supplements or in clinical settings. (C) 2016 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)208-211
Number of pages4
JournalBioorganic & Medicinal Chemistry Letters
Issue number2
Publication statusPublished - 15 Jan 2017


  • 2-Methyl-1,4-naphthoquinone
  • Vitamin K
  • Phylloquinone
  • Menaquinone
  • Osteocalcin
  • ACID
  • FOOD

Cite this