Substituted Vitamin K Epoxide Analogues. New Competitive Inhibitors and Substrates of Vitamin K1 Epoxide Reductase

Robert P. Ryall, Dhirendra L. Nandi, Richard B Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

2- and 3-substituted vitamin K 2,3-epoxide analogues were synthesized and tested as inactivators, inhibitors, and substrates for beef liver microsomal vitamin K1 epoxide reductase. 2-(X)-3-phytyl-l,4-naphthoquinone 2,3-epoxides, where X is hydroxymethyl, chloromethyl, fluoromethyl, difluoromethyl, and formyl were all competitive inhibitors, but none was an inactivator. Only the 2-hydroxymethyl analogue was reduced to a quinone that was stable enough under the conditions of the experiment to be detected. Vitamin K1 epoxide analogues with modified phytyl chains (1'-hydroxy, 3'-fluoro with isomerized double bond, 1'-hydroxy and 1'-fluoro with saturated double bond, and the corresponding unsubstituted chains) were synthesized. All of the analogues were competitive inhibitors of vitamin K1 epoxide reductase. The nonfluorinated analogues also were shown to be substrates, being reduced to the corresponding quinone without enzyme inactivation. At least one other enzyme besides vitamin K1 epoxide reductase in beef liver microsomes also metabolizes all of these analogues.

Original languageEnglish (US)
Pages (from-to)1790-1797
Number of pages8
JournalJournal of Medicinal Chemistry
Volume33
Issue number6
DOIs
StatePublished - Jan 1 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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