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

Abstract

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.

2023 Julius Axelrod Symposium: Plant-Derived Molecules Acting on G Protein-Coupled Receptors

“…Starting from an active natural ligand, the classical way to improve the effect of the molecule is to perform an SAR analysis. This technique has been employed to design and synthetize more potent and selective bile acid derivatives for the recently discovered TGR5 receptor (Sato et al, 2008) but also to identify a new class of coumarin-based GCRs activators and inhibitors (Fu et al, 2022). To further improve already well-documented plant-derived molecules with proven effects on human health, a large-scale library and fast screening technique are used like for the AT1 receptor and ETA receptor.…”

Daphnetin, a Coumarin with Anticancer Potential against Human Melanoma: In Vitro Study of Its Effective Combination with Selected Cytostatic Drugs

“…Each of the natural compounds is characterized by a different chemical structure and various biological activities. An interesting group of compounds are coumarins; it is estimated that, so far, about 1300 substances of this group have been isolated from plants, fungi or bacteria [ 6 , 7 ].…”

Daphnetin, a Coumarin in Genus Stellera Chamaejasme Linn: Chemistry, Bioactivity and Therapeutic Potential

“…[39] Currently, more than 1,300 natural-based coumarins have been isolated and identified in a variety of plants, bacteria and fungi. [40,41] Many drugs containing a coumarin moiety, such as esculetin (1), [42] isofraxidin (2), [43] psoralen (3), [44] warfarin (4), [45] acenocoumarin (5), [46] phenprocoumon (6), [46] dicumarol (7), [47] calanolide A (8), [48] cloricromen (9), [49] novobiocin (10), [50] etc. have been employed as potential therapeutic agents for clinical treatment (Figure 1).…”

“…Coumarins were firstly found in tonka bean ( Dipteryx odorata Wild ) and distributed in about 150 species of 30 families such as Rutaceae , Umbelliferae , Clusiaceae , Guttiferae , Caprifoliaceae , Oleaceae , Nyctaginaceae and Apiaceae [39] . Currently, more than 1,300 natural‐based coumarins have been isolated and identified in a variety of plants, bacteria and fungi [40,41] . Many drugs containing a coumarin moiety, such as esculetin ( 1 ), [42] isofraxidin ( 2 ), [43] psoralen ( 3 ), [44] warfarin ( 4 ), [45] acenocoumarin ( 5 ), [46] phenprocoumon ( 6 ), [46] dicumarol ( 7 ), [47] calanolide A ( 8 ), [48] cloricromen ( 9 ), [49] novobiocin ( 10 ), [50] etc .…”