title: Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists.
abstract: Tetrahydroquinoline (THQ)-type compounds are a class of potential larvicides against mosquitoes. The structure-activity relationships (SAR) of these compounds were previously investigated (Smith et al., Bioorg. Med. Chem. Lett. 2003, 13, 1943-1946), and one of cis-forms (with respect to the configurations of 2-methyl and 4-anilino substitutions on the THQ basic structure) was stereoselectively synthesized. However, the absolute configurations of C2 and C4 were not determined. In this study, four THQ-type compounds with cis configurations were synthesized, and two were submitted for X-ray crystal structure analysis. This analysis demonstrated that two enantiomers are packed into the crystal form. We synthesized the cis-form of the fluorinated THQ compound, according to the published method, and the enantiomers were separated via chiral HPLC. The absolute configurations of the enantiomers were determined by X-ray crystallography. Each of the enantiomers was tested for activity against mosquito larvae in vivo and competitive binding to the ecdysone receptor in vitro. Compared to the (2S,4R) enantiomer, the (2R,4S) enantiomer showed 55 times higher activity in the mosquito larvicidal assay, and 36 times higher activity in the competitive receptor binding assay.
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Harada
authors.affiliation: Mitsubishi Tanabe Pharma Corporation, Kashima 3-16-89, Yodogawa, Osaka 532-8505, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hiramatsu
authors.affiliation: Mitsubishi Tanabe Pharma Corporation, Kashima 3-16-89, Yodogawa, Osaka 532-8505, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Miyagawa
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: naka@kais.kyoto-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004440:Ecdysone / Q000819:agonists*; D007313:Insecta; D008958:Models, Molecular; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D004440:Ecdysone; C542964:1,2,3,4-tetrahydroquinoline
keywords: Ecdysone; Larvicide; Mosquito; Stereospecificity; Tetrahydroquinoline