Feng Jie, Du Xin, Liu Hui, Sui Xin, Zhang Chen, Tang Yun, Zhang Jingyan
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.
Dalton Trans. 2014 Jul 28;43(28):10930-9. doi: 10.1039/c4dt01111b.
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.
由于金属配合物具有独特的性质，非甾体抗炎药（NSAIDs）与金属离子的配位作用可以提高NSAIDs的药效。然而，许多金属-NSAID配合物的结构尚未得到很好的表征；因此，这些配合物的作用机制和药理作用尚未完全明确。在本研究中，合成了三种锰-甲芬那酸（Mn-甲芬那酸）配合物并对其结构进行了表征，并研究了它们的药理作用。我们发现，这三种Mn-甲芬那酸配合物表现出比母体配体甲芬那酸（78.67 μM）更高的脂氧合酶（LOX-1）抑制活性（IC50值分别为16.79、38.63和28.06 μM）。更重要的是，Mn-甲芬那酸配合物的高抑制活性与其空间排列密切相关，空间排列决定了它们与LOX-1的相互作用。Mn-甲芬那酸配合物与LOX-1的计算机对接证实了实验结果：较小的Mn-甲芬那酸配合物倾向于在底物结合位点与LOX-1竞争性结合，这也类似于配体甲芬那酸的结合，而体积较大的金属配合物则非竞争性地抑制酶活性。此外，Mn-甲芬那酸配合物表现出比配体甲芬那酸更高的抗氧化活性。Mn-甲芬那酸配合物较高的抗氧化活性显然源于配合物的锰中心。因此，我们得出结论，Mn-甲芬那酸配合物通过改变与酶的相互作用模式来提高活性，和/或利用金属离子提高抗氧化能力，从而增强甲芬那酸的抗炎活性。这项工作提供了实验证据，表明金属-NSAID配合物凭借其独特的空间排列，能够更特异性、更有效地与靶酶相互作用，这优于它们的母体NSAID配体。
