Synthesis of Coumarin Derivatives: A New Class of Coumarin-Based G Protein-Coupled Receptor Activators and Inhibitors

Polymers

Shiyi Wang¹  Ruilong Sheng²  Zian Wang³  Ruihua Guo³  Zhe Fu³  Xiaojing Sun³  Sijin Hang³  Na Li³  Linjie Zhang³  Wenhui Wu³  Fang Wang⁴ 

[1] AIEN Institute, Shanghai Ocean University, Shanghai 201306, China;CQM—Centro de Química da Madeira, Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal;College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China;School Basic Medicine, Shanghai University of Medicine and Health Science, Shanghai 201318, China;

关键词: coumarin;    G protein-coupled receptors;    synthesis;    structure–activity relationships;   

DOI  :  10.3390/polym14102021

来源: DOAJ

【 摘 要 】

To expand the range of daphnetin-based inhibitors/activators used for targeting G protein-coupled receptors (GPCRs) in disease treatment, twenty-five coumarin derivatives 1–25, including 7,8-dihydroxycoumarin and 7-hydroxycoumarin derivatives with various substitution patterns/groups at C3-/4- positions, were synthesized via mild Pechmann condensation and hydroxyl modification. The structures were characterized by ¹H NMR, ¹³C NMR and ESI-MS. Their inhibition or activation activities relative to GPCRs were evaluated by double-antibody sandwich ELISA (DAS–ELISA) in vitro. The results showed that most of the coumarin derivatives possessed a moderate GPCR activation or inhibitory potency. Among them, derivatives 14, 17, 18, and 21 showed a remarkable GPCR activation potency, with EC₅₀ values of 0.03, 0.03, 0.03, and 0.02 nM, respectively. Meanwhile, derivatives 4, 7, and 23 had significant GPCR inhibitory potencies against GPCRs with IC₅₀ values of 0.15, 0.02, and 0.76 nM, respectively. Notably, the acylation of hydroxyl groups at the C-7 and C-8 positions of 7,8-dihydroxycoumarin skeleton or the etherification of the hydroxyl group at the C-7 position of the 7-hydroxycoumarin skeleton could successfully change GPCRs activators into inhibitors. This work demonstrated a simple and efficient approach to developing coumarin derivatives as remarkable GPCRs activators and inhibitors via molecular diversity-based synthesis.

【 授权许可】

Unknown