title: Manganese-mefenamic acid complexes exhibit high lipoxygenase inhibitory activity.
abstract: The coordination of non-steroidal anti-inflammatory drugs (NSAIDs) to metal ions could improve the pharmaceutical efficacy of NSAIDs due to the unique characteristics of metal complexes. However, the structures of many metal-NSAID complexes are not well characterized; the functional mechanism and pharmaceutical effect of these complexes thus are not fully understood. In this work, three manganese-mefenamic acid (Mn-mef) complexes were synthesized and structurally characterized, and their pharmaceutical effect was investigated. We found that the three Mn-mef complexes exhibit higher lipoxygenase (LOX-1) inhibitory activity (IC50 values are 16.79, 38.63 and 28.06 μM, respectively) than the parent ligand mefenamic acid (78.67 μM). More importantly, the high inhibitory activity of the Mn-mef complexes is closely related to their spatial arrangements, which determine their interaction with LOX-1. Computer docking of the Mn-mef complexes with the LOX-1 confirms the experimental results: smaller Mn-mef complexes tend to bind competitively to LOX-1 at the substrate binding site, which is also analogous to the binding of the ligand mefenamic acid, while the bulky metal complexes inhibit the enzyme activity un-competitively. In addition, the Mn-mef complexes exhibit higher anti-oxidant activity than the ligand mefenamic acid. The higher anti-oxidant activity of the Mn-mef complexes apparently originated from the manganese centre of the complexes. We thus conclude that Mn-mef complexes enhance the anti-inflammatory activity of mefenamic acid by increasing their activity via changing their interaction mode with the enzymes, and/or by improving their anti-oxidant ability using metal ions. This work provides experimental evidence that with the unique spatial arrangements, metal-NSAID complexes could interact with the target enzymes more specifically and efficiently, which is superior to their parent NSAID ligand.
authors.affiliation: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P. R. China. jyzhang@ecust.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Feng
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Sui
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Jingyan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008345:Manganese / Q000737:chemistry*; D013058:Mass Spectrometry; D008528:Mefenamic Acid / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D051127:Scavenger Receptors, Class E / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D056831:Coordination Complexes; D016859:Lipoxygenase Inhibitors; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D008528:Mefenamic Acid; D008345:Manganese