2-(Fluoromethyl)-3-phytyl-1,4-naphthoquinone and its 2,3-epoxide. Inhibition of vitamin K epoxide reductase.
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.
Silverman
R B
RB
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113.
Oliver
J S
JS
D000818:Animals; D001667:Binding, Competitive; D002384:Catalysis; D002417:Cattle; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases
C060962:2-(fluoromethyl)-3-phytyl-1,4-naphthoquinone; C060963:2-(fluoromethyl)-3-(phytyl)-1,4-naphthoquione 2,3-epoxide; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases