Anti-inflammatory activity of superoxide dismutase mimics functionalized with cell-penetrating peptides

Mathieu, Émilie; Bernard, Anne-Sophie; Ching, H. Y. Vincent; Somogyi, Andréa; Medjoubi, Kadda; Fores, Jennifer Rodon; Bertrand, Hélène; Vincent, Amandine; Guerquin‐Kern, Jean‐Luc; Scheitler, Andreas; Seksik, Philippe; Delsuc, Nicolas; Policar, Clotilde

doi:10.1039/c9dt04619d

Cited by 19 publications

(38 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although it penetrates in this model, no activity was observed for this negatively charged porphyrin. Interestingly too, this study suggests that M40403 and EUK134 penetrate into cells and confirmed the previous results reported for Mn1 [9,103,107]. The different activities observed here may be related to different cellular localizations.…”

Section: Resultssupporting

confidence: 91%

“…Because the ligand is toxic for the cells [9], the pro-inflammatory response observed may be due to the toxicity of the non-coordinated ligand. Note that in this model, MnCl 2 was previously assayed and found to be not active or proinflammatory [9,103,107]. After incubation at a higher concentration (100 µM), as expected, M40403 and MnTnBuOE-2-PyP 5+ were found more active than at 10 µM.…”

Section: Resultssupporting

confidence: 74%

“…Besides, it has been shown that such inflammatory reaction is mediated by oxidative stress [105,106]. HT29-MD2 cells were thus incubated in presence of LPS and the antioxidants at non-toxic concentrations: 10 and 100 µM (Figure S4, SI) [9,103,107]. In this assay, 6h incubations were required to observe a significant inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models

Vincent

Thauvin

Quévrain

et al. 2021

Journal of Inorganic Biochemistry

Self Cite

View full text Add to dashboard Cite

Oxidative stress that results from an imbalance between the concentrations of reactive species (RS) and antioxidant defenses is associated with many pathologies. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase are among the key enzymes that maintain the low nanomolar physiological concentrations of superoxide and hydrogen peroxide. The increase in the levels of these species and their progeny could have deleterious effects. In this context, chemists have developed SOD and CAT mimics to supplement them when cells are overwhelmed with oxidative stress. However, the beneficial activity of such molecules in cells depends not only on their intrinsic catalytic activities but also on their stability in biological context, their cell penetration and their cellular localization. We have employed cellular assays to characterize several compounds that possess SOD and CAT activities and have been frequently used in cellular and animal models. We used cellular assays that address SOD and CAT activities of the compounds. Finally, we determined the effect of compounds on the suppression of the inflammation in HT29-MD2 cells challenged by lipopolysaccharide. When the assay requires penetration inside cells, the SOD mimics Mn(III) mesotetrakis(N-(2′-nbutoxyethyl)pyridinium-2-yl)porphyrin (MnTnBuOE-2-PyP 5+ ) and Mn(II) dichloro [(4aR,13aR,17aR,21aR)-

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultssupporting

confidence: 74%

See 1 more Smart Citation

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models

Vincent

Thauvin

Quévrain

et al. 2021

Journal of Inorganic Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Manganese SOD mimics described in the literature include complexes with ligands such as porphyrins [14,[22][23][24][25][26][27][28], salens [29,30], cyclic polyamines [11,[31][32][33][34][35][36][37] phthalocyanines [38], or peptidyl ligands [39][40][41]. We have been developing a 1,2ethanediamine-centered ligand, called EnPI2 [42], inspired by the MnSOD-active site, with a coordination sphere consisting of three imidazoles and one phenolate, easily amenable to synthetic modulation [43][44][45][46]. Mn(II)-EnPI2, labeled Mn1, is a positively charged complex with a redox potential close to the optimal value for superoxide dismutation [42,44].…”

Section: Introductionmentioning

confidence: 99%

“…To date, the cellular accumulation of SOD mimics was usually examined by measuring the increase in the overall intracellular content in manganese using ICP-MS [46,[50][51][52], EPR [44][45][46], Raman [53], X-ray absorption spectroscopy [36], and X-ray fluorescence imaging [13,36,[44][45][46] or by detecting the cellular uptake using UV quantification of Mn porphyrin via the Soret band area [16,54] or of fluorescently labeled SOD mimics using laser confocal microscopy [36,40,46,55]. At best, these techniques enable determining the intracellular distribution of the ligand, complexes, and/or Mn.…”

Section: Introductionmentioning

confidence: 99%

Inertness of Superoxide Dismutase Mimics Mn(II) Complexes Based on an Open-Chain Ligand, Bioactivity, and Detection in Intestinal Epithelial Cells

Schanne

Zoumpoulaki

Gazzah

et al. 2022

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

Oxidative stress is known to play a major role in the pathogenesis of inflammatory bowel diseases (IBDs), and, in particular, superoxide dismutase (SODs) defenses were shown to be weakened in patients suffering from IBDs. SOD mimics, also called SOD mimetics, as low-molecular-weight complexes reproducing the activity of SOD, constitute promising antioxidant catalytic metallodrugs in the context of IBDs. A Mn(II) complex SOD mimic (Mn1) based on an open-chain diaminoethane ligand exerting antioxidant and anti-inflammatory effects on an intestinal epithelial cellular model was shown to experience metal exchanges between the manganese center and metal ions present in the biological environment (such as Zn(II)) to some degrees. As the resulting complexes (mainly Zn(II)) were shown to be inactive, improving the kinetic inertness of Mn(II) complexes based on open-chain ligands is key to improve their bioactivity in a cellular context. We report here the study of three new Mn(II) complexes resulting from Mn1 functionalization with a cyclohexyl and/or a propyl group meant to limit, respectively, (a) metal exchanges and (b) deprotonation of an amine from the 1,2-diaminoethane central scaffold. The new manganese-based SOD mimics display a higher intrinsic SOD activity and also improved kinetic inertness in metal ion exchange processes (with Zn(II), Cu(II), Ni(II), and Co(II)). They were shown to provide anti-inflammatory and antioxidant effects in cells at lower doses than Mn1 (down to 10 μM). This improvement was due to their higher inertness against metal-assisted dissociation and not to different cellular overall accumulations. Based on its higher inertness, the SOD mimic containing both the propyl and the cyclohexyl moieties was suitable for intracellular detection and quantification by mass spectrometry, quantification, that was achieved by using a 13C-labeled Co-based analog of the SOD mimics as an external heavy standard.

show abstract

Deciphering the Metal Speciation in Low‐Molecular‐Weight Complexes by IMS‐MS: Application to the Detection of Manganese Superoxide Dismutase Mimics in Cell Lysates

et al. 2022

Self Cite

View full text Add to dashboard Cite

The detection and quantification of exogenous metal complexes are crucial to understanding their activity in intricate biological media. MnII complexes are difficult to detect and quantify because of low association constants, and high lability. The superoxide dismutase (SOD) mimic (or mimetic) labelled Mn1 is based on a 1,2‐di‐aminoethane functionalized with imidazole and phenolate and has good intrinsic anti‐superoxide, antioxidant and anti‐inflammatory activities in lipopolysaccharide (LPS)‐activated intestinal epithelial HT29‐MD2 cells, similar to that of its propylated analogue labelled Mn1P. Ion mobility spectrometry‐mass spectrometry (IMS‐MS) is a powerful technique for separating low molecular weight (LMW) metal complexes and can even separate complexes with the same ligand but bound to different divalent metal cations with similar ionic radii. We demonstrated the intracellular presence of the Mn1 and Mn1P complexes, at least partly intact, in lysates of cells incubated with the complexes and estimated the intracellular Mn1P concentration using a Co‐13C6 analogue.

show abstract

Anti-inflammatory activity of superoxide dismutase mimics functionalized with cell-penetrating peptides

Abstract: A superoxide dismutase mimic was functionalized with three peptides: -R9, -RRWWRRWRR or -Fx-r-Fx-K (MPP). They were studied in intestinal epithelial cells in an inorganic cellular chemistry approach: quantification, distribution and bio-activity.

Cited by 19 publications

References 61 publications

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models

Evaluation of the compounds commonly known as superoxide dismutase and catalase mimics in cellular models

Inertness of Superoxide Dismutase Mimics Mn(II) Complexes Based on an Open-Chain Ligand, Bioactivity, and Detection in Intestinal Epithelial Cells

Deciphering the Metal Speciation in Low‐Molecular‐Weight Complexes by IMS‐MS: Application to the Detection of Manganese Superoxide Dismutase Mimics in Cell Lysates

Contact Info

Product

Resources

About