TY - JOUR
T1 - Structural requirement and stereospecificity of tetrahydroquinolines as potent ecdysone agonists
AU - Kitamura, Seiya
AU - Harada, Toshiyuki
AU - Hiramatsu, Hajime
AU - Shimizu, Ryo
AU - Miyagawa, Hisashi
AU - Nakagawa, Yoshiaki
N1 - Funding Information:
We thank Dr. Qing X. Li of the University of Hawaii for reviewing the manuscript. The Culex pipiens eggs were kindly provided by Sumitomo Chemical Co. Aedes albopictus cells (NIAS-AeAl-2) were obtained from the GeneBank of National Institute of Agrobiological Sciences (NIAS). This study was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 25450070 ) and the 21st century COE program for Innovative Food and Environmental Studies Pioneered by Entomomimetic Sciences. Dr. Toshiyuki Harada was a recipient of a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientist.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
KW - Ecdysone
KW - Larvicide
KW - Mosquito
KW - Stereospecificity
KW - Tetrahydroquinoline
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U2 - 10.1016/j.bmcl.2014.02.043
DO - 10.1016/j.bmcl.2014.02.043
M3 - Article
C2 - 24630413
AN - SCOPUS:84897404183
SN - 0960-894X
VL - 24
SP - 1715
EP - 1718
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 7
ER -