Inhibition of TNF-α stimulated nuclear factor-kappa B (NF-κB) activation by cyclometalated platinum(<scp>ii</scp>) complexes

Liu, Jia; Sun, Raymond Wai‐Yin; Leung, Chung‐Hang; Lok, Chun‐Nam; Che, Chi‐Ming

doi:10.1039/c1cc15317j

Cited by 18 publications

(15 citation statements)

References 28 publications

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“…In addition to cisplatin and its derivatives, the study of neutral platinum complexes with cyclometalated 2,6-diphenylpyridine ligand (C^N^C-H 2 ) has been an area of considerable interest 29 and numerous pincer platinum complexes with anti-cancer properties have been described 12,30. Notably, this includes work showing tridentate 2,6-diphenylpyridine square planar platinum complexes are able to inhibit NF-κB-dependent gene transcription 31. Advantages of cyclometalated Pt complexes for bio-applications include the fact many are neutral molecules and so will not influence the extracellular/intracellular charge balance 32 while certain complexes emit from long-lived metal-to-ligand or ligand-to-ligand charge transfer states, providing a convenient method to track intracellular localization using fluorescence microscopy 33.…”

Section: Introductionmentioning

confidence: 99%

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

Zhu¹,

Zhang²,

Luo³

et al. 2019

Theranostics

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Platinum complexes have been used for anti-cancer propose for decades, however, their high side effects resulting from damage to healthy cells cannot be neglected and prevent further clinical utilisation. Here, we designed a cyclometalated platinum (II) complex that can bind the endogenous nuclear factor-κB (NF-κB) protein. Employing detailed colocalization studies in co-culture cell line models, we show that by binding to NF-κB, the platinum (II) complex is capable of upregulated nuclear translocation specifically in cancer but not normal cells, thereby impairing cancer proliferation without disturbing healthy cells. In a murine tumour model, the platinum (II) complex prevents tumour growth to a greater extent than cisplatin and with considerably lower side-effects and kidney damage. Considering its weak damage to normal cells combined with high toxicity to cancer cells, this NF-κB-binding platinum complex is a potential anti-cancer candidate and acts to verify the strategy of hijacking endogenous trans-nuclear proteins to achieve cancer-cell specificity and enhance therapeutic indices.

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Section: Introductionmentioning

confidence: 99%

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

Zhu¹,

Zhang²,

Luo³

et al. 2019

Theranostics

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“…33,34 Therefore, square-planar cyclometalated complexes with -conjugated ligands seem to be suitable systems due to the electronic features of the C- bond ( donor) and the aromatic fragment ( acceptor). Platinum (II) complexes containing C^N-bidentate or C^N^N, N^C^N, C^N^C, C^N^S-tridentate chelating ligands have been investigated recently because of the potential use as anti-cancer agents, [35][36][37][38][39][40] imaging species for biomolecules 37,[40][41][42][43] as well as for the development of new tuneable optoelectronic molecular devices, [44][45][46][47][48][49] dye-sensitized solar cells 50,51 and sensor manufacturing. 52,53 Most of these applications can be related to the outstanding photophysical behaviour of these complexes.…”

Section: Introductionmentioning

confidence: 99%

Heteropolynuclear Pt(II)–M(I) Clusters with a C^∧N^∧C Biscyclometalated Ligand

et al. 2012

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The mononuclear complex [(EtO 2 C-C^N^C)Pt(dmpyz)] (1) (dmpyz = 2,5-dimethylpyrazine) has been synthesised by reaction of [(EtO 2 C-C^N^C)Pt(dmso)] (A) with dmpyz in 1:1 molar ratio in dichloromethane. Complex 1 is the precursor for preparing the homodinuclear complex [{(EtO 2 C-C^N^C)Pt} 2 (-dmpyz)] (2) and the heterotrinuclear clusters [{(EtO 2 C-C^N^C)Pt(dmpyz)} 2 M]X (M= Cu, X= PF 6 (3); M= Ag, X= BF 4 (4)). Compounds 1, 2 and 4 were studied by X-ray diffraction methods. In the crystal packing of 1 and 2, the molecules display short intermolecular ••• contacts, which control the solid state emissive behavior. X-ray study on 4 shows two [Pt 2 Ag] sandwich-type clusters in the asymmetric unit, both with the two square-planar "(R-CNC)Pt(dmpyz)" moieties stabilized by two Pt→Ag donoracceptor bonds as well as by  1-and  2-Ag-C interactions. Intramolecular - contacts were found between the pyridine rings of the CNC ligands within the same Pt 2 Ag cluster. 1 H and 195 Pt NMR studies confirm that the Pt 2 M cluster is also retained in solution at room temperature. 195 Pt NMR spectra of 3 and 4 show signals shifted significantly downfield when comparing to that for the monomer (1), which is attributed to presence of Pt-M dative bonds. At lower temperatures (T = 193 K), the copper derivative definitely falls apart, whereas the silver one still holds up unbroken. In solid state at 77 K, compounds 1-4 give red emissions arising from 3  excited states due to the intra-or intermolecular - contacts observed in the crystal structures. As expected, in glassy solutions (77 K), compound 3 displays analogous emissions to those from the starting material (1). Complexes 1 and 2 show structured emission bands which are particularly sensitive to the ex (HE and LE). In contrast, 4 displays an unstructured emission at 680 nm with a shoulder at 556 nm, both are not dependent on the ex. DFT and TDDFT computational studies have been performed on 1 and 2 which support the conclusions drawn from the photophysical studies.

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“…PPIs have been regarded as challenging targets for small molecules due to their lack of similarity with conventional ligand-molecule binding sites 28 . In this context, our group has previously developed Group 9 metal-based inhibitors of the PPIs of TNF-α and BRD4 22 29 . Therefore, in this work we set out to investigate whether metal complexes could be used as inhibitors of the HIF-1α–p300 PPI, for which no metal-based inhibitor has yet been reported in the literature.…”

Section: Discussionmentioning

confidence: 99%

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction

Yang

Wang

et al. 2017

Sci Rep

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The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α–p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α–p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 μM. Complex 1 interfered with the HIF-1α–p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.

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Inhibition of TNF-α stimulated nuclear factor-kappa B (NF-κB) activation by cyclometalated platinum(ii) complexes

Abstract: Cyclometalated platinum(II) complexes [Pt(II)(C^N^N)(C≡NR)](+) (HC^N^N = 6-phenyl-2,2'-bipyridyl) display significant inhibition towards TNF-α stimulated NF-κB-dependent gene transcription at concentrations down to the micromolar range.

Cited by 18 publications

References 28 publications

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

Heteropolynuclear Pt(II)–M(I) Clusters with a C^∧N^∧C Biscyclometalated Ligand

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction

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Inhibition of TNF-α stimulated nuclear factor-kappa B (NF-κB) activation by cyclometalated platinum(ii) complexes

Abstract: Cyclometalated platinum(II) complexes [Pt(II)(C^N^N)(C≡NR)](+) (HC^N^N = 6-phenyl-2,2'-bipyridyl) display significant inhibition towards TNF-α stimulated NF-κB-dependent gene transcription at concentrations down to the micromolar range.

Cited by 18 publications

References 28 publications

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

NF-κB hijacking theranostic Pt(ll) complex in cancer therapy

Heteropolynuclear Pt(II)–M(I) Clusters with a C∧N∧C Biscyclometalated Ligand

Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction

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Resources

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Heteropolynuclear Pt(II)–M(I) Clusters with a C^∧N^∧C Biscyclometalated Ligand