title: Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors: Hana Bashir
authors: HB
authors: Shawish
authors: Institute of Biological Sciences at the Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors: Wan Ying
authors: WY
authors: Wong
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Yi Li
authors: YL
authors: Wong
authors: Institute of Biological Sciences at the Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors: Sheng Wei
authors: SW
authors: Loh
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Chung Yeng
authors: CY
authors: Looi
authors: Department of Medical Microbiology at the Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Pouya
authors: P
authors: Hassandarvish
authors: Department of Medical Microbiology at the Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Alicia Yi Ling
authors: AY
authors: Phan
authors: Department of Medical Microbiology at the Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Won Fen
authors: WF
authors: Wong
authors: School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, P. R. China; Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors: Hao
authors: H
authors: Wang
authors: Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors: Ian C
authors: IC
authors: Paterson
authors: Institute of Biological Sciences at the Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors: Chee Kwee
authors: CK
authors: Ea
authors: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: Mohd Rais
authors: MR
authors: Mustafa
authors: Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
authors: Mohd Jamil
authors: MJ
authors: Maah
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D002460:Cell Line; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009532:Nickel / Q000737:chemistry*; D021381:Protein Transport; D013882:Thiosemicarbazones / Q000737:chemistry*; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D056831:Coordination Complexes; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013882:Thiosemicarbazones; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D009532:Nickel; D002351:Carrageenan; D051550:I-kappa B Kinase