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

Bioorg Chem. 2020 Nov:104:104342. doi: 10.1016/j.bioorg.2020.104342. Epub 2020 Oct 6.

Abstract

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.

Keywords: Daphnetin derivatives; G protein-coupled receptors; Structure-activity relationships; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Mice
  • Molecular Structure
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism*
  • Structure-Activity Relationship
  • Umbelliferones / chemical synthesis
  • Umbelliferones / chemistry
  • Umbelliferones / pharmacology*

Substances

  • Receptors, G-Protein-Coupled
  • Umbelliferones
  • daphnetin