GSK137647

Sulfonamides are prominently featured in organic synthesis and medicinal chem.Yet, a general synthetic platform for the modular construction of aryl sulfonamides remains elusive.Herein, a metal-free photoredox-catalyzed three-component construction of aryl sulfonamides via aryl sulfonyl ammonium salt intermediate, which was generated in situ via SET event, has been established.A variety of structurally diverse primary, secondary, and tertiary aryl sulfonamides were synthesized rapidly from abundant amines or sodium azide under mild conditions.Notably, the primary aliphatic amine, which remains challenging in the Cu-catalyzed protocols, worked well in this approach.Moreover, aryl sulfonyl fluoride can be accessed smoothly as well, using potassium hydrogen fluoride as the nucleophile.The potential utility of this conversion is demonstrated in the facile construction of three bioactive drug compoundsPreliminary mechanistic studies have revealed that the aryl sulfonyl radical and aryl sulfonyl ammonium salt are the key intermediates in this mechanistically innovative methodol.

To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization.

Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry.

The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments.

Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.