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.
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.
Oh
Keimei
K
Department of Biotechnology, Faculty of Bio-resource Sciences, Akita Prefectural University, Akita 010-0195, Japan. jmwang@akita-pu.ac.jp
Shimura
Yoichiro
Y
Ishikawa
Kyoko
K
Ito
Yudai
Y
Asami
Tadao
T
Murofushi
Noboru
N
Yoshizawa
Yuko
Y
D002210:Caprylates / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C515148:8-(1-(2,4-dichlorophenyl)-2-imidazol-1-ylethoxy)octanoic acid heptyl ester; D002210:Caprylates; D007093:Imidazoles; D019746:Intramolecular Oxidoreductases; C021377:hydroperoxide isomerase