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Synthesis and structure–activity relationships of novel warfarin derivatives

Authors
Journal
Bioorganic & Medicinal Chemistry
0968-0896
Publisher
Elsevier
Publication Date
Volume
15
Issue
6
Identifiers
DOI: 10.1016/j.bmc.2007.01.014
Keywords
  • 4-Hydroxycoumarin
  • Warfarin
  • Ferulenol
  • Vitamin K Epoxide Reductase
Disciplines
  • Biology
  • Medicine
  • Political Science

Abstract

Abstract 4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers ∼22 times more potent inhibition than warfarin and is ∼1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K.

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