Rebouças Júlio S, Spasojević Ivan, Tjahjono Daryono H, Richaud Arlette, Méndez Francisco, Benov Ludmil, Batinić-Haberle Ines
Department of Radiation Oncology, Duke University Medical School, Durham, NC 27710, USA.
Dalton Trans. 2008 Mar 7(9):1233-42. doi: 10.1039/b716517j. Epub 2008 Jan 7.
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 (MnTTriMAP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylpyrazolium-4-yl)porphyrin (MnTDM-4-PzP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylimidazolium-2-yl)porphyrin (MnTDM-2-ImP(5+)), and the ortho and para methylpyridinium complexes Mn(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (MnTM-4-PyP(5+)) and Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP(5+)). Both Mn(III)/Mn(II) reduction potential and SOD activity within the series follow the order: MnTTriMAP(5+)<MnTDM-4-PzP(5+)<MnTM-4-PyP(5+)<MnTM-2-PyP(5+)<MnTDM-2-ImP(5+). The kinetic salt effect (KSE) on the catalytic rate constant for superoxide dismutation (k(cat)) indicates that the electrostatic contribution to the O(2)*(-) dismutation is the greatest with MnTM-2-PyP(5+) and follows the order: MnTM-4-PyP(5+)<MnTDM-4-PzP(5+) approximately MnTDM-2-ImP(5+)<MnTM-2-PyP(5+). The KSE observed on k(cat) suggests that the charges are relatively confined within specific regions of the aryl rings. Whereas the charges in imidazolium, pyrazolium, and MnTM-4-PyP(5+) 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)/Mn(II) reduction potential (and/or SOD activity) and meso-aryl fragment softness descriptors for nucleophilic (s(f)(+)) and radical (s(f)(o)) attacks was observed. MnTDM-4-PzP(5+) and MnTM-4-PyP(5+) did not protect SOD-deficient E. coli grown aerobically, which is in agreement with their low k(cat). MnTM-2-PyP(5+) and MnTDM-2-ImP(5+) have similar high k(cat), but MnTDM-2-ImP(5+) 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.
我们在此评估正电荷分布对锰卟啉作为氧化还原调节剂的体外和体内性质的影响，这些锰卟啉具有相同的 +5 总电荷且空间位阻需求最小：锰（III）中 - 四（三甲基苯胺 -4- 基）卟啉（MnTTriMAP(5+)）、锰（III）中 - 四（N，N'- 二甲基吡唑 -4- 基）卟啉（MnTDM - 4 - PzP(5+)）、锰（III）中 - 四（N，N'- 二甲基咪唑 -2- 基）卟啉（MnTDM - 2 - ImP(5+)），以及邻位和对位甲基吡啶鎓配合物锰（III）中 - 四（N - 甲基吡啶 -4- 基）卟啉（MnTM - 4 - PyP(5+)）和锰（III）中 - 四（N - 甲基吡啶 -2- 基）卟啉（MnTM - 2 - PyP(5+)）。该系列中锰（III）/锰（II）还原电位和超氧化物歧化酶（SOD）活性遵循以下顺序：MnTTriMAP(5+)<MnTDM - 4 - PzP(5+)<MnTM - 4 - PyP(5+)<MnTM - 2 - PyP(5+)<MnTDM - 2 - ImP(5+)。超氧化物歧化反应催化速率常数（k(cat)）的动力学盐效应（KSE）表明，对 O(2)*(-) 歧化的静电贡献以 MnTM - 2 - PyP(5+) 最大，且遵循以下顺序：MnTM - 4 - PyP(5+)<MnTDM - 4 - PzP(5+)≈MnTDM - 2 - ImP(5+)<MnTM - 2 - PyP(5+)。在 k(cat) 上观察到的 KSE 表明电荷相对局限于芳环的特定区域内。咪唑鎓、吡唑鎓和 MnTM - 4 - PyP(5+) 化合物中的电荷与卟啉环共面分布，而 MnTM - 2 - PyP(5+) 的电荷在平面上方或下方，这更有效地将带负电荷的超氧化物导向锰卟啉的轴向位置，并导致最高的 KSE。这模拟了在 SOD 酶本身中观察到的隧道效应。中 - 芳基取代基引起的电子扰动对锰中心反应性的调节可以通过密度泛函理论（DFT）计算来解释，由此观察到锰（III）/锰（II）还原电位（和 / 或 SOD 活性）与亲核（s(f)(+)）和自由基（s(f)(o)）攻击的中 - 芳基片段软度描述符之间的相关性。MnTDM - 4 - PzP(5+) 和 MnTM - 4 - PyP(5+) 不能保护需氧生长的超氧化物歧化酶缺陷型大肠杆菌，这与其低 k(cat) 一致。MnTM - 2 - PyP(5+) 和 MnTDM - 2 - ImP(5+) 具有相似的高 k(cat)，但 MnTDM - 2 - ImP(5+) 对大肠杆菌的保护作用明显较小，可能是由于其体积较大、细胞摄取减少和 / 或观察到的毒性。电荷更靠近金属中心的位置和空间电荷定位增加了化合物的体外和体内 SOD 活性。
