Diindolylmethane Derivatives: Potent Agonists of the Immunostimulatory Orphan G Protein-Coupled Receptor GPR84

Abstract

The G protein-coupled receptor GPR84, which is activated by (hydroxy)fatty acids, is highly expressed on immune cells. Recently, 3,3'-diindolylmethane was identified as a heterocyclic, nonlipid-like GPR84 agonist. We synthesized a broad range of diindolylmethane derivatives by condensation of indoles with formaldehyde in water under microwave irradiation. The products were evaluated at the human GPR84 in cAMP and β-arrestin assays. Structure-activity relationships (SARs) were steep. 3,3'-Diindolylmethanes bearing small lipophilic residues at the 5- and/or 7-position of the indole rings displayed the highest activity in cAMP assays, the most potent agonists being di(5-fluoro-1H-indole-3-yl)methane (38, PSB-15160, EC 80.0 nM) and di(5,7-difluoro-1H-indole-3-yl)methane (57, PSB-16671, EC 41.3 nM). In β-arrestin assays, SARs were different, indicating biased agonism. The new compounds were selective versus related fatty acid receptors and the arylhydrocarbon receptor. Selected compounds were further investigated and found to display an ago-allosteric mechanism of action and increased stability in comparison to the lead structure.

A rapid, efficient and versatile green synthesis of 3,3'-diindolylmethanes

“…Organic reactions in water as a reaction medium offer many advantages, including low cost, safe handling and environment compatibility. Recently we developed a new procedure for the synthesis of DIMs in aqueous media under microwave irradiation at 100 o C. 25 No catalyst was used for the reaction of indoles with formaldehyde, while sodium dodecylsulfate (SDS) was employed as an emulsifier for the reaction of indoles with aliphatic and aromatic aldehydes. 25 In continuation of our research program, we have now further improved the synthetic access to a large variety of target compounds by developing an operationally simple, fast and efficient green procedure for the synthesis of DIMs.…”

“…23 Recently DIM and its analogues have been identified and characterized as potent agonists of the immunostimulatory orphan G protein-coupled receptor GPR84. 24,25 The goal of the present study was to develop a straightforward access to a broad range of synthetic derivatives and analogues of DIM for subsequent biological studies.…”

Enzymatic approach to cascade synthesis of bis(indolyl)methanes in pure water

“…Bis(indolyl)methanes make great contributions in the elds of pharmacological industry and material science. They may act as agonists of the immunostimulatory orphan G protein-coupled receptor GPR84, 1 as antagonists of Leishmania donovani promastigotes as well as axenic amastigotes, 2 and also as probes for monitoring the interactions of related molecules with transport and response-mediating proteins. 3 In addition, bis(indolyl) methanes play a brilliant role in the treatment of prostate cancer, 4 colon cancer, 5 pancreatic cancer 6 and breast cancer.…”

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water

“…In our continuous effort of synthesizing indole derivatives [29][30][31], herein, we report an efficient synthesis of multiple halogensubstituted (1H-indol-3-yl)methanol derivatives in the presence of potassium carbonate and tetrabutylphophonium bromide, which mediate the reaction in water through the formation of the interface between organic and aqueous phases. The advantageous of this reaction include high yields, no column chromatography, broad substrate scope, multiscale synthesis, and recyclable of the catalyst ( Figure 2C).…”