title: Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro.
abstract: 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.
authors.affiliation: School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
authors.forename: Liuqiang
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Qi
authors.initials: Q
authors.lastname: Jia
authors.forename: Jinwen
authors.initials: J
authors.lastname: Xu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D057889:Iridoid Glycosides; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy; D008517:Phytotherapy; D028321:Plant Preparations / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011714:Pyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012977:Sodium Nitrite / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D001617:beta-Glucosidase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006027:Glycosides; D057889:Iridoid Glycosides; D028321:Plant Preparations; D011714:Pyrans; D014409:Tumor Necrosis Factor-alpha; C033249:harpagoside; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001617:beta-Glucosidase; D012977:Sodium Nitrite; C033250:harpagide