Syntheses and evaluation of daphnetin derivatives as novel G protein-coupled receptor inhibitors and activators

• Published in: Bioorganic chemistry 2020-11, Vol.104, p.104342, Article 104342
• Main Authors: Wang, Yinan, Wang, Jiangming, Fu, Zhe, Sheng, Ruilong, Wu, Wenhui, Fan, Junting, Guo, Ruihua
• Format: Article
• Language: English
• Subjects: Animals; Daphnetin derivatives; Dose-Response Relationship, Drug; G protein-coupled receptors; Mice; Molecular Structure; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - metabolism; Structure-Activity Relationship; Structure-activity relationships; Synthesis; Umbelliferones - chemical synthesis; Umbelliferones - chemistry; Umbelliferones - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104342

A series of daphnetin (7,8-dihydroxycoumarin) derivatives 1–22 were synthesized including sixteen new compounds (1–5, 7–14, 18, 21 and 22) and six known compounds (6, 15–17, 19 and 20). Their pharmacological activities on G protein-coupled receptors (GPCRs) were evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Daphnetin derivatives with various substitution patterns/groups were obtained from inhibitors to activators on GPCRs. Derivatives 2–5, 8, 15, 16 and 18–20 possessed moderate activation potency on GPCRs. Among them, derivatives 3–5, 16 and 19 presented significant activation potency on GPCRs with EC50 values in the range of 1.18–1.91 nM. Derivatives 6, 11, 14 and 18 showed significant inhibitory potency on GPCRs with IC50 values in the range of 1.26–1.38 nM. Moreover, the structure-activity relationships (SARs) of daphnetin derivatives were discussed in detail. The new daphnetic-based GPCRs activators and inhibitors shave potentials as future drug candidates for the treatment of metabolic diseases. [Display omitted] •We synthesized a series of analogues at C-7, C-8, and C-3/C-4 position of daphnetin.•The analogues were firstly evaluated for their bioactivities on GPCRs.•The derivatives had different bioactivities potency ranging from inhibitors to activator. A series of daphnetin (7,8-dihydroxycoumarin) derivatives 1–22 were synthesized including sixteen new compounds (1–5, 7–14, 18, 21 and 22) and six known compounds (6, 15–17, 19 and 20). Their pharmacological activities on G protein-coupled receptors (GPCRs) were evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Daphnetin derivatives with various substitution patterns/groups were obtained from inhibitors to activators on GPCRs. Derivatives 2–5, 8, 15, 16 and 18–20 possessed moderate activation potency on GPCRs. Among them, derivatives 3–5, 16 and 19 presented significant activation potency on GPCRs with EC50 values in the range of 1.18–1.91 nM. Derivatives 6, 11, 14 and 18 showed significant inhibitory potency on GPCRs with IC50 values in the range of 1.26–1.38 nM. Moreover, the structure-activity relationships (SARs) of daphnetin derivatives were discussed in detail. The new daphnetic-based GPCRs activators and inhibitors have potentials as future drug candidates for the treatment of metabolic diseases.