title: Synthesis of 2-methyl-1,4-naphthoquinones with higher gamma-glutamyl carboxylase activity than MK-4 both in vitro and in vivo.
abstract: 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 WKY rats receiving a vitamin K-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.
authors.affiliation: R&D Group VitaK, Maastricht University, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands. Electronic address: c.vermeer@vitak.com.
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.affiliation: R&D Group VitaK, Maastricht University, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands.
authors.forename: Cynthia
authors.initials: C
authors.lastname: van 't Hoofd
authors.affiliation: R&D Group VitaK, Maastricht University, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands.
authors.forename: Marjo H J
authors.initials: MHJ
authors.lastname: Knapen
authors.affiliation: R&D Group VitaK, Maastricht University, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands.
authors.forename: Sofia
authors.initials: S
authors.lastname: Xanthoulea
mesh_terms: D000818:Animals; D019735:Carbon-Carbon Ligases / Q000378:metabolism*; D045744:Cell Line, Tumor; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D015675:Osteocalcin / Q000096:biosynthesis; D011516:Prothrombin / Q000032:analysis; D011921:Rats, Inbred WKY; D014812:Vitamin K / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014813:Vitamin K Deficiency / Q000188:drug therapy
chemical_list: D020536:Enzyme Activators; D015675:Osteocalcin; D024482:Vitamin K 2; D014812:Vitamin K; C030814:menatetrenone; D011516:Prothrombin; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase
keywords: 2-Methyl-1,4-naphthoquinone; Menaquinone; Osteocalcin; Phylloquinone; Vitamin K