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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.

SUBMITTER: Fei X

PROVIDER: S-EPMC6152652 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Fei Xiang X Je In-Gyu IG Shin Tae-Yong TY Kim Sang-Hyun SH Seo Seung-Yong SY

Molecules (Basel, Switzerland) 20170529 6

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 ...[more]

PMID: 28555061

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Project description:BackgroundRisk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine.MethodsStroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, and 7 days post-ischemia; sham mice received the same surgery but no MCAO. In this work, we evaluated whether worsened outcomes after experimental stroke in aged mice were associated with age-related changes in mast cells, histamine levels, and histamine receptor expression in the gut, brain, and plasma.ResultsWe found increased numbers of mast cells in the gut and the brain with aging. Using the middle cerebral artery occlusion (MCAO) model of ischemic stroke, we demonstrate that stroke leads to increased numbers of gut mast cells and gut histamine receptor expression levels. These gut-centric changes are associated with elevated levels of HA and other pro-inflammatory cytokines including IL-6, G-CSF, TNF-α, and IFN-γ in the peripheral circulation. Our data also shows that post-stroke gut inflammation led to a significant reduction of mucin-producing goblet cells and a loss of gut barrier integrity. Lastly, gut inflammation after stroke is associated with changes in the composition of the gut microbiota as early as 24-h post-stroke.ConclusionAn important theme emerging from our results is that acute inflammatory events following ischemic insults in the brain persist longer in the aged mice when compared to younger animals. Taken together, our findings implicate mast cell activation and histamine signaling as a part of peripheral inflammatory response after ischemic stroke, which are profound in aged animals. Interfering with histamine signaling orally might provide translational value to improve stroke outcome.

Dataset Information

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

Publications

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

Similar Datasets

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