Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors

Eur J Med Chem. 2012 Nov;57:134-42. doi: 10.1016/j.ejmech.2012.09.006. Epub 2012 Sep 11.

Abstract

All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC(50) = 0.8 μM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC(50) = 1.3 μM). The IC(50) variations of the farnesyl derivatives for HLO-1 (1.3 to ∼75 μM) were much higher than that observed for SLO (0.8-5.8 μM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with Fe(III)-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 15-Lipoxygenase / chemistry*
  • Coumarins / chemical synthesis*
  • Coumarins / chemistry
  • Humans
  • Hydrogen Bonding
  • Kinetics
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Molecular Docking Simulation
  • Protein Prenylation
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Soybean Proteins / antagonists & inhibitors
  • Soybean Proteins / chemistry*
  • Soybeans / chemistry
  • Soybeans / enzymology
  • Structure-Activity Relationship

Substances

  • Coumarins
  • Lipoxygenase Inhibitors
  • Recombinant Proteins
  • Soybean Proteins
  • ALOX15 protein, human
  • Arachidonate 15-Lipoxygenase