Asymmetric synthesis and stereochemical structure-activity relationship of (R)- and (S)-8-[1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethoxy] octanoic acid heptyl ester, a potent inhibitor of allene oxide synthase

Bioorg Med Chem. 2008 Feb 1;16(3):1090-5. doi: 10.1016/j.bmc.2007.10.095. Epub 2007 Nov 4.

Abstract

The preparation of both enantiomers of 8-[1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethoxy] octanoic acid heptyl ester (JM-8686), a potent inhibitor of allene oxide synthase, has been achieved using 2,4-dichlorophenacyl bromide as a starting material. The key step was the asymmetric reduction of 1-(2,4-dichlorophenyl)-2-imidazol-1-yl-ethanone with chiral BINAL-H. The products were purified by chiral high-performance liquid chromatography (HPLC) to afford pure (R)-JM-8686 and (S)-JM-8686. The inhibitory activities and binding affinities of these enantiomers toward allene oxide synthase were determined. We found that the inhibition potency of (R)-JM-8686 is approximately 200 times greater than that of (S)-JM-8686, with IC(50) values of approximately 5+/-0.2 nM and 950+/-18 nM, respectively. The dissociation constants of (R)-JM-8686 and (S)-JM-8686 with respect to the recombinant allene oxide synthase were approximately 1.4+/-0.3 microM and 4.8+/-0.6 microM, respectively.

MeSH terms

  • Caprylates / chemistry*
  • Caprylates / pharmacology*
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism*
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 8-(1-(2,4-dichlorophenyl)-2-imidazol-1-ylethoxy)octanoic acid heptyl ester
  • Caprylates
  • Imidazoles
  • Intramolecular Oxidoreductases
  • hydroperoxide isomerase