Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tuebingen , Auf der Morgenstelle 8, D-72076 Tuebingen, Germany.
J Nat Prod. 2014 Jun 27;77(6):1445-51. doi: 10.1021/np500198g. Epub 2014 May 20.
The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.
微粒体前列腺素 E2 合酶（mPGES-1）是环氧化酶（COX）衍生的 PGH2 生成前列腺素（PG）E2 的终末酶。我们之前发现，mPGES-1 被乳香酸（IC50=3-30 μM）抑制，乳香酸是抗炎疗法乳香中存在的生物活性三萜酸。在这里，我们表明，除了乳香酸之外，乳香中分离出的其他已知三萜酸（即，三齿栗酸、羽扇豆醇酸和罗布酸）也具有抑制 mPGES-1 的作用，且活性更强。特别是，3α-乙酰氧基-8,24-二烯三齿栗酸（6）和 3α-乙酰氧基-7,24-二烯三齿栗酸（10）在无细胞测定中以 IC50=0.4 μM 的浓度抑制 mPGES-1 活性。构效关系研究和对接模拟揭示了与 mPGES-1 及其共底物谷胱甘肽的具体结构相关相互作用。三萜酸对 COX-1 和 COX-2 的影响很小（IC50>10 μM）。鉴于 mPGES-1 在炎症中的关键作用以及乳香提取物中高活性三萜酸的丰富性，我们的研究结果进一步证明了乳香制剂的抗炎潜力，并揭示了三齿栗酸、罗布酸和羽扇豆醇酸的新的、有效的生物活性。
