The vitamin E derivative α-amplexichromanol as anti-inflammatory lead inspired from traditional African medicine
The vitamin E derivative α-amplexichromanol as anti-inflammatory lead inspired from traditional African medicine
复制标题
维生素 E 衍生物 α-amplexichromanol 作为抗炎铅，灵感源自非洲传统医学
DOI：
10.1055/s-0039-3400108
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发表时间：
2019
期刊：
影响因子：
2.7
通讯作者：
Koeberle
中科院分区：
文献类型：
--
作者：
Neukirch;Raasch;Seraphin;Helesbeux;Roviezzo;Richomme;Koeberle
藤黄果种子传统上用于非洲医学，以其抗菌、抗氧化和抗炎活性而闻名。抗炎成分和强效 5-脂氧合酶抑制剂藤黄酸 [1] 的结构优化产生了 α-amplexichromanol (α-AC)，它是内源性维生素 E 代谢物的半合成类似物，可介导维生素 E 的免疫功能 [2]。与藤黄酸和生物活性维生素 E 代谢物 α-T-13ʹ-COOH 相比，α-AC 具有优异的 5-脂氧合酶抑制活性。在这里，我们展示了 α-AC 在体内限制了小鼠腹膜炎和实验性哮喘的炎症，并使用肝脏芯片模型解决了该化合物预期更高的代谢稳定性问题。 α-AC 显着降低 5-脂氧合酶衍生的白三烯 (LT) C 4 水平以及炎症细胞浸润和支气管高反应性。血浆、肺和支气管中的脂质介质谱发生了全面改变，与 α-T-13ʹ-COOH 相比，在最后一次腹膜内给药后六天内在肺中检测到了 α-AC。虽然 α-T-13ʹ-COOH 可通过 β-氧化有效降解，但 α-AC 主要被硫酸化，但不会被截短。我们的结果表明 α-AC 是一种有前途的天然产物先导化合物，具有口服活性，并且与藤黄酸和内源性维生素 E 代谢物相比，代谢似乎更稳定。
The nut seeds of Garcinia kola are traditionally used in African medicine and known for their anti-microbial, anti-oxidative and anti-inflammatory activities. Structural optimization of the anti-inflammatory ingredient and potent 5-lipoxygenase inhibitor garcinoic acid [1] yielded α-amplexichromanol (α-AC) which is a semi-synthetic analog of endogenous vitamin E metabolites that mediate immune functions of vitamin E [2]. α-AC possesses superior 5-lipoxygenase-inhibitory activity as compared to garcinoic acid and the bioactive vitamin E metabolite α-T-13ʹ-COOH. Here we show that α-AC limits inflammation in murine peritonitis and experimental asthma in vivo and address the compound’s expected higher metabolic stability using a liver-on-chip model. α-AC significantly reduced 5-lipoxygenase-derived leukotriene (LT) C 4 levels along with inflammatory cell infiltration and bronchial hyperreactivity. Lipid mediator profiles in plasma, lung and bronchia are comprehensively altered and α-AC was detected in lung up to six days after the last ip administration in contrast to α-T-13ʹ-COOH. While α-T-13ʹ-COOH is efficiently degraded by β-oxidation, α-AC is predominantly sulfated but not truncated. Our results indicate α-AC as a promising natural product-inspired lead that is orally active and seemingly metabolically more stable as compared to garcinoic acid and endogenous vitamin E metabolites.