Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation

Hana Bashir Shawish, Wan Ying Wong, Yi Li Wong, Sheng Wei Loh, Chung Yeng Looi, Pouya Hassandarvish, Alicia Yi Ling Phan, Won Fen Wong, Hao Wang, Ian C. Paterson, Chee Kwee Ea, Mohd Rais Mustafa, Mohd Jamil Maah

Research output: Contribution to journalArticle

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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; H3 L1, CH 3; H3L2, C6H5; H 3L3 and C2H5; H3L 4) 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 IκBβ 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.

Original languageEnglish (US)
Article numbere100933
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 30 2014

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Thiosemicarbazones
transcriptional activation
Nickel
anti-inflammatory activity
nickel
Transcriptional Activation
Anti-Inflammatory Agents
Carrageenan
carrageenan
cytokines
transition elements
Molecular Docking Simulation
Genes
Cytokines
luciferase
Transcription
Luciferases
Inbred C57BL Mouse
HeLa Cells
active sites

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shawish, H. B., Wong, W. Y., Wong, Y. L., Loh, S. W., Looi, C. Y., Hassandarvish, P., ... Maah, M. J. (2014). Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation. PLoS One, 9(6), [e100933]. https://doi.org/10.1371/journal.pone.0100933

Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation. / 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.

In: PLoS One, Vol. 9, No. 6, e100933, 30.06.2014.

Research output: Contribution to journalArticle

Shawish, HB, Wong, WY, Wong, YL, Loh, SW, Looi, CY, Hassandarvish, P, Phan, AYL, Wong, WF, Wang, H, Paterson, IC, Ea, CK, Mustafa, MR & Maah, MJ 2014, 'Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation', PLoS One, vol. 9, no. 6, e100933. https://doi.org/10.1371/journal.pone.0100933
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. / Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation. In: PLoS One. 2014 ; Vol. 9, No. 6.
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AU - Wong, Yi Li

AU - Loh, Sheng Wei

AU - Looi, Chung Yeng

AU - Hassandarvish, Pouya

AU - Phan, Alicia Yi Ling

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