Asymmetric synthesis of tetrahydroquinoline-type ecdysone agonists and QSAR for their binding affinity against Aedes albopictus ecdysone receptors.
QSAR
asymmetric synthesis
ecdysone
mosquito
tetrahydroquinoline
Journal
Pest management science
ISSN: 1526-4998
Titre abrégé: Pest Manag Sci
Pays: England
ID NLM: 100898744
Informations de publication
Date de publication:
Jan 2019
Jan 2019
Historique:
received:
11
06
2018
revised:
27
07
2018
accepted:
30
07
2018
pubmed:
3
8
2018
medline:
3
1
2019
entrez:
3
8
2018
Statut:
ppublish
Résumé
Tetrahydroquinolines (THQs) are a class of non-steroidal ecdysone agonists that specifically bind to mosquito ecdysone receptors (EcR). The THQ scaffold contains two chiral centers at the C-2 and C-4 positions, resulting in four stereoisomers. We have previously shown that the (2R,4S)-isomers are the most biologically active; however, the lack of a practical synthetic method for these isomers has hampered further structure-activity studies. In this study, a chiral phosphoric acid-catalyzed Povarov reaction was employed to develop a facile asymmetric synthesis of THQs with a (2R,4S)-configuration, which allowed the preparation of a 40-compound library of enantiopure THQs. Evaluation of their binding affinity against Aedes albopictus EcR, followed by quantitative structure-activity relationship (QSAR) analyses, uncovered the physicochemical properties of THQs that are important for the ligand-receptor interaction. The most potent THQ derivative was twofold more active than the molting hormone, 20-hydroxyecdysone. The QSAR results provide valuable information for the rational design of novel mosquito-specific ecdysone agonists. © 2018 Society of Chemical Industry.
Sections du résumé
BACKGROUND
BACKGROUND
Tetrahydroquinolines (THQs) are a class of non-steroidal ecdysone agonists that specifically bind to mosquito ecdysone receptors (EcR). The THQ scaffold contains two chiral centers at the C-2 and C-4 positions, resulting in four stereoisomers. We have previously shown that the (2R,4S)-isomers are the most biologically active; however, the lack of a practical synthetic method for these isomers has hampered further structure-activity studies.
RESULTS
RESULTS
In this study, a chiral phosphoric acid-catalyzed Povarov reaction was employed to develop a facile asymmetric synthesis of THQs with a (2R,4S)-configuration, which allowed the preparation of a 40-compound library of enantiopure THQs. Evaluation of their binding affinity against Aedes albopictus EcR, followed by quantitative structure-activity relationship (QSAR) analyses, uncovered the physicochemical properties of THQs that are important for the ligand-receptor interaction. The most potent THQ derivative was twofold more active than the molting hormone, 20-hydroxyecdysone.
CONCLUSION
CONCLUSIONS
The QSAR results provide valuable information for the rational design of novel mosquito-specific ecdysone agonists. © 2018 Society of Chemical Industry.
Substances chimiques
Insect Proteins
0
Quinolines
0
Receptors, Steroid
0
ecdysone receptor
0
Ecdysone
3604-87-3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115-124Subventions
Organisme : JSPS KAKENHI
ID : JP17J01486
Organisme : JSPS KAKENHI
ID : JP16K07625
Informations de copyright
© 2018 Society of Chemical Industry.