School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
Bioorg Med Chem. 2011 Aug 15;19(16):4882-6. doi: 10.1016/j.bmc.2011.06.069. Epub 2011 Jun 29.
Harpagide (1) and harpagoside (2) are two iridoid glycosides existing in many medicinal plants. Although they are believed to be the main bioactive compounds related to the anti-inflammatory efficacy of these plants, the mechanisms of their anti-inflammatory activities remain unclear. The results of our present study showed that 1 and 2 had no effects on inhibitions of cyclooxygenase (COX)-1/2 enzyme activity, tumor necrosis factor-α (TNF-α) release, and nitric oxide (NO) production in vitro. However, the hydrolyzed products of 1 and 2 with β-glucosidase treatment showed a significant inhibitory effect on COX-2 activity at 2.5-100 μM in a concentration-dependent manner. Our further study revealed that the hydrolyzed 2 product was structurally the same as the hydrolyzed 1 product (H-harpagide (3)). The structure of 3 was 2-(formylmethyl)-2,3,5-trihydroxy-5-methylcyclopentane carbaldehyde, with a backbone similar to prostaglandins and COX-2 inhibitors such as celecoxib. All of them have a pentatomic ring with two adjacent side chains. The result of molecular modeling and docking study showed that 3 could bind to the COX-2 active domain well through hydrophobic and hydrogen-bonding interactions, whereas 1 and 2 could not, implying that the hydrolysis of the glycosidic bond of 1 and 2 is a pre-requisite step for their COX-2 inhibitory activity.
裂环环烯醚萜苷（1）和裂环环烯醚萜苷（2）是存在于许多药用植物中的两种裂环环烯醚萜苷。尽管它们被认为是与这些植物抗炎功效相关的主要生物活性化合物，但它们的抗炎活性机制仍不清楚。我们目前的研究结果表明，1 和 2 对环氧化酶（COX）-1/2 酶活性、肿瘤坏死因子-α（TNF-α）释放和体外一氧化氮（NO）产生的抑制没有影响。然而，用β-葡萄糖苷酶处理 1 和 2 的水解产物在 2.5-100 μM 浓度范围内以浓度依赖性方式对 COX-2 活性表现出显著抑制作用。我们的进一步研究表明，水解产物 2 的结构与水解产物 1（H-裂环环烯醚萜苷（3））相同。3 的结构为 2-（甲酰甲基）-2,3,5-三羟基-5-甲基环戊烷甲醛，其骨架与前列腺素和 COX-2 抑制剂（如塞来昔布）相似。它们都有一个五原子环和两个相邻的侧链。分子建模和对接研究的结果表明，3 可以通过疏水和氢键相互作用与 COX-2 活性域很好地结合，而 1 和 2 则不能，这表明 1 和 2 的糖苷键的水解是其 COX-2 抑制活性的先决条件。
