2-(Fluoromethyl)-3-phytyl-1,4-naphthoquinone and its 2,3-epoxide. Inhibition of vitamin K epoxide reductase

J Med Chem. 1989 Sep;32(9):2138-41. doi: 10.1021/jm00129a019.

Abstract

2-(Fluoromethyl)-3-phytyl-1,4-naphthoquinone (7) was synthesized from the known compound 2-bromo-3-methyl-1,4-dimethoxynaphthalene by N-bromosuccinimide bromination of the 3-methyl group, conversion to the corresponding 3-fluoromethyl compound with silver fluoride, attachment of the 3-phytyl substitutent via the lithium diaryl cuprate and phytyl bromide, and then silver oxide oxidation to 7. Epoxidation with basic hydrogen peroxide gave the corresponding 2,3-oxide (1) in a very low yield. Compound 1 was not a time-dependent inhibitor of beef liver microsomal vitamin K epoxide reductase, but it was a competitive, reversible inhibitor. It was not possible to determine if 1 was a substrate for the enzyme because the expected product of reduction, namely 7, rapidly decomposed under the assay conditions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Catalysis
  • Cattle
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Vitamin K 1 / analogs & derivatives*
  • Vitamin K 1 / chemical synthesis
  • Vitamin K 1 / pharmacology
  • Vitamin K Epoxide Reductases

Substances

  • 2-(fluoromethyl)-3-phytyl-1,4-naphthoquinone
  • 2-(fluoromethyl)-3-(phytyl)-1,4-naphthoquione 2,3-epoxide
  • Vitamin K 1
  • Mixed Function Oxygenases
  • Vitamin K Epoxide Reductases