Keimei Oh, Yoichiro Shimura, Kyoko Ishikawa, Yudai Ito, Tadao Asami, Noboru Murofushi, Yuko Yoshizawa
Department of Biotechnology, Faculty of Bio-resource Sciences, Akita Prefectural University, Akita 010-0195, Japan. jmwang@akita-pu.ac.jp
Bioorganic & medicinal chemistry 2008 Feb 1The 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.
Keimei Oh, Yoichiro Shimura, Kyoko Ishikawa, Yudai Ito, Tadao Asami, Noboru Murofushi, Yuko Yoshizawa. 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. Bioorganic & medicinal chemistry. 2008 Feb 1;16(3):1090-5
PMID: 18024044
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