Shawish Hana Bashir, Wong Wan Ying, Wong Yi Li, Loh Sheng Wei, Looi Chung Yeng, Hassandarvish Pouya, Phan Alicia Yi Ling, Wong Won Fen, Wang Hao, Paterson Ian C, Ea Chee Kwee, Mustafa Mohd Rais, Maah Mohd Jamil
Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
Institute of Biological Sciences at the Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
PLoS One. 2014 Jun 30;9(6):e100933. doi: 10.1371/journal.pone.0100933. eCollection 2014.
The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity.
METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.
CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.
硫代卡巴腙的生物学特性已有广泛报道。已知将一些过渡金属（如铁、镍和铜）引入硫代卡巴腙配合物可增强其生物学效应。在本研究中，我们将镍（II）离子引入具有N4-取代基团H3L（H；H3L1、CH3；H3L2、C6H5；H3L3和C2H5；H3L4）的硫代卡巴腙中，并研究其潜在的抗炎活性。
方法/主要发现：合成并表征了四种配体（1-4）及其各自含镍的配合物（5-8）。测试了合成化合物对NF-κB核转位、促炎细胞因子分泌和NF-κB反式激活活性的影响。进一步评估了活性化合物在体内抑制角叉菜胶诱导的急性炎症的能力。还通过分子对接分析预测了活性化合物的潜在结合靶点。
结论/意义：在所有测试的合成化合物中，我们发现配合物[Ni(H2L1)(PPh3)]Cl（5）（配合物5）在LPS刺激的RAW264.7细胞以及TNFα刺激的HeLa S3细胞中，能有效抑制IκBα降解和NF-κB p65核转位。此外，配合物5显著下调LPS或TNFα诱导的NF-κB靶基因的转录，包括编码促炎细胞因子TNFα、IFNβ和IL6的基因。荧光素酶报告基因检测证实配合物5抑制NF-κB的反式激活活性。此外，配合物5对野生型C57BL/6小鼠角叉菜胶诱导的爪肿胀形成的抑制作用也支持了其抗炎作用。有趣的是，分子对接研究表明配合物5可能与IKKβ的活性位点相互作用。综上所述，我们认为配合物5是一种具有强效抗炎作用的新型NF-κB抑制剂。
