Synthesis of Gallic Acid Analogs as Histamine and Pro-Inflammatory Cytokine Inhibitors for Treatment of Mast Cell-Mediated Allergic Inflammation

Abstract

Gallic acid (3,4,5-trihydroxybenzoic acid), is a natural product found in various foods and herbs that are well known as powerful antioxidants. Our previous report demonstrated that it inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. In this report, various amide analogs of gallic acid have been synthesized by introducing different amines through carbodiimide-mediated amide coupling and Pd/C-catalyzed hydrogenation. These compounds showed a modest to high inhibitory effect on histamine release and pro-inflammatory cytokine expression. Among them, the amide bearing (S)-phenylglycine methyl ester 3d was found to be more active than natural gallic acid. Further optimization yielded several (S)- and (R)-phenylglycine analogs that inhibited histamine release in vitro. Our findings suggest that some gallamides could be used as a treatment for allergic inflammatory diseases.

Gallic acid attenuates allergic airway inflammation via suppressed interleukin‐33 and group 2 innate lymphoid cells in ovalbumin‐induced asthma in mice

“…Using both in vitro and in vivo experiments, we found that gallic acid regulates ILC2s via MyD88‐mediated IL‐33 expression, reducing IL‐5 and IL‐13 secretion of ILC2s and, consequently, improving pulmonary inflammation and AHR. Several studies have shown that gallic acid could function as an anti‐allergic agent in treating some allergic disorders, including asthma; however, to our knowledge, this is the first report showing that it may have anti‐asthma effects by regulating ILC2 activity.…”

“…As an effective anti‐inflammatory agent, gallic acid, or its synthetic analogs, has been found to inhibit release of histamine and pro‐inflammatory cytokines and also agonize G protein–coupled receptor‐35 (a proven target of asthma drugs such as cromolyn and nedocromil) . This limited evidence has suggested a possible role for gallic acid in asthma treatment, but few studies have been undertaken to test this possibility.…”

“…Gallic acid, which is derived from many plants, is an effective anti‐inflammatory agent and has been tested in a number of inflammatory conditions . Mechanistically, gallic acid has been reported to act on various kinds of cells and alter the secretion of many cytokines . Given these characteristics, it is believed that gallic acid could be beneficial for asthma treatment.…”

SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling

“…GA, a part of EGCG, was shown to have inhibitory effects on mast cell-mediated allergic inflammation in our previous studies, and we have generated various derivatives of GA to improve its pharmacological effectiveness (10,11). As mentioned above, to strengthen the effectiveness of GA, SG-SP1 was designed from GA (12). In this study, we aimed to compare the anti-allergic effects of SG-SP1 with those of GA.…”

“…The residue was purified by flash column chromatography on a silica gel (ethyl acetate/n-hexane = 1:3) to produce the desired amide. Compound 3d was identified as SG-SP1 (12).…”