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Redox modulation of oxidative stress by Mn porphyrin-based therapeutics: The effect of charge distribution
Reboucas J.S.a, Spasojevic I.a, Tjahjono D.H.b, Richaud A.c, Mendez F.c, Benov L.d, Batinic-Haberle I.a
a Department of Radiation Oncology, Duke University, Medical School, United States
b School of Pharmacy, Bandung Institute of Technology, Indonesia
c Departamento de Química, División de Ciencias Básicas e Ingenierías, Universidad Autónoma Metropolitana-Iztapalapa, Mexico
d Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait
[vc_row][vc_column][vc_row_inner][vc_column_inner][vc_separator css=”.vc_custom_1624529070653{padding-top: 30px !important;padding-bottom: 30px !important;}”][/vc_column_inner][/vc_row_inner][vc_row_inner layout=”boxed”][vc_column_inner width=”3/4″ css=”.vc_custom_1624695412187{border-right-width: 1px !important;border-right-color: #dddddd !important;border-right-style: solid !important;border-radius: 1px !important;}”][vc_empty_space][megatron_heading title=”Abstract” size=”size-sm” text_align=”text-left”][vc_column_text]We evaluate herein the impact of positive charge distribution on the in vitro and in vivo properties of Mn porphyrins as redox modulators possessing the same overall 5+ charge and of minimal stericity demand: Mn(iii) meso-tetrakis(trimethylanilinium-4-yl)porphyrin (MnTTriMAP5+), Mn(iii) meso-tetrakis(N,N′-dimethylpyrazolium-4-yl)porphyrin (MnTDM-4-PzP5+), Mn(iii) meso-tetrakis(N,N′- dimethylimidazolium-2-yl)porphyrin (MnTDM-2-ImP5+), and the ortho and para methylpyridinium complexes Mn(iii) meso-tetrakis(N-methylpyridinium-4-yl) porphyrin (MnTM-4-PyP5+) and Mn(iii) meso-tetrakis(N- methylpyridinium-2-yl)porphyrin (MnTM-2-PyP5+). Both Mn III/MnII reduction potential and SOD activity within the series follow the order: MnTTriMAP5+ < MnTDM-4-PzP5+ < MnTM-4-PyP5+ < MnTM-2-PyP5+ < MnTDM-2-ImP 5+. The kinetic salt effect (KSE) on the catalytic rate constant for superoxide dismutation (kcat) indicates that the electrostatic contribution to the O2̇- dismutation is the greatest with MnTM-2-PyP5+ and follows the order: MnTM-4-PyP5+ < MnTDM-4-PzP5+ ∼ MnTDM-2-ImP5+ < MnTM-2-PyP 5+. The KSE observed on kcat suggests that the charges are relatively confined within specific regions of the aryl rings. Whereas the charges in imidazolium, pyrazolium, and MnTM-4-PyP5+ compounds are distributed in-plane with the porphyrin ring, the charges of MnTM-2-PyP 5+ are either above or below the plane, which channels the negatively-charged superoxide toward the axial positions of the Mn porphyrin more efficiently, and leads to the highest KSE. This mimics the tunneling effect observed in the SOD enzymes themselves. The modulation of the reactivity of the Mn center by the electronic perturbations caused by the meso-aryl substituent could be explained by DFT calculation, whereby a correlation between the Mn III/MnII reduction potential (and/or SOD activity) and meso-aryl fragment softness descriptors for nucleophilic (sf +) and radical (sfo) attacks was observed. MnTDM-4-PzP5+ and MnTM-4-PyP5+ did not protect SOD-deficient E. coli grown aerobically, which is in agreement with their low kcat. MnTM-2-PyP5+ and MnTDM-2-ImP5+ have similar high kcat, but MnTDM-2-ImP5+ was significantly less protective to E. coli, probably due to its bulkier size, decreased cellular uptake, and/or observed toxicity. The placement of charges closer to the metal center and spatial charge localization increases both the in vitro and the in vivo SOD activity of the compound. © The Royal Society of Chemistry.[/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Author keywords" size="size-sm" text_align="text-left"][vc_column_text]Mesotetrakis,Redox modulators,Spatial charge localization,Therapeutics[/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Indexed keywords" size="size-sm" text_align="text-left"][vc_column_text][/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="Funding details" size="size-sm" text_align="text-left"][vc_column_text][/vc_column_text][vc_empty_space][vc_separator css=".vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}"][vc_empty_space][megatron_heading title="DOI" size="size-sm" text_align="text-left"][vc_column_text]https://doi.org/10.1039/b716517j[/vc_column_text][/vc_column_inner][vc_column_inner width=”1/4″][vc_column_text]Widget Plumx[/vc_column_text][/vc_column_inner][/vc_row_inner][/vc_column][/vc_row][vc_row][vc_column][vc_separator css=”.vc_custom_1624528584150{padding-top: 25px !important;padding-bottom: 25px !important;}”][/vc_column][/vc_row]