- Inhibitor daphnetin derivative and application and pharmaceutical composition thereof
-
The invention provides an inhibitor daphnetin derivative and application and a pharmaceutical composition thereof. The daphnetin derivative (1-13) or the pharmaceutically acceptable salt or solvent compound thereof is shown as the following formula. The p
- -
-
Paragraph 0048-0056
(2020/11/25)
-
- Syntheses and evaluation of daphnetin derivatives as novel G protein-coupled receptor inhibitors and activators
-
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.
- Wang, Yinan,Wang, Jiangming,Fu, Zhe,Sheng, Ruilong,Wu, Wenhui,Fan, Junting,Guo, Ruihua
-
-
- Synthesis and structure-activity relationship of daphnetin derivatives as potent antioxidant agents
-
In this study, daphnetin 1 was chosen as the lead compound, and C-3 or C-4-substituted daphnetins were designed and synthesized to explore the potential relationship between the antioxidant activities and the chemical structures of daphnetin derivatives. The antioxidant activities of the generated compounds were evaluated utilizing the free radical scavenging effect on 2,2-diphenyl-1-picrylhydrazyl, 2,2-azinobis-(3-ethylbenzthiazoline-6-sulfonate) cation, and the ferric reducing power assays, and were then compared with those of the standard antioxidant Trolox. The results showed that the catechol group was the key pharmacophore for the antioxidant activity of the daphnetins. The introduction of an electron-withdrawing hydrophilic group at the C-4 position of daphnetin enhanced the antioxidative capacity, but this trend was not observed for C-3 substitution. In addition, introduction of a a hydrophobic phenyl group exerted negative effects on the antioxidant activity in both the C-3 and C-4 substitutions. Among all of the derivatives tested, the most powerful antioxidant was 4-carboxymethyl daphnetin (compound 9), for which the strongest antioxidant activity was observed in all of the assays. In addition, compound 9 also displayed strong pharmaceutical properties in the form of metabolic stability. To summarize, compound 9 holds great potential to be developed as an antioxidant agent with excellent antioxidant activity and proper pharmacokinetic behavior.
- Xia, Yangliu,Chen, Chen,Liu, Yong,Ge, Guangbo,Dou, Tongyi,Wang, Ping
-
-