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Experimental and DFT mechanistic studies on the design and synthesis of cationic porphyrins led to a superb SOD mimic: MnTnBuOE-2-PyP5+

Mn(III) ortho N-alkylpyridylporphyrins are potent superoxide dismutase mimics, peroxynitrite reduction catalysts, overall ROS/RNS scavengers, and effective redox signaling modulators.1, 2 The lead ethyl (MnTE-2-PyP5+) and n-hexyl (MnTnHex-2-PyP5+) compounds have been employed in many oxidative stress-related diseases and injuries, such as cancer, stroke, and radiation injuries.1, 2 Whereas the intrinsic antioxidant potency of Mn porphyrins (MnPs) is physico-chemically controlled, their biological activity relies also on their toxicity, bioavailability, and biodistribution, which depend on factors such as size and lipophilicity. The incorporation of oxygenated alkyl side-chains, such as PEG and methoxyethyl (MeOEt), on Mn(III) ortho N-pyridylporphyrins led to species of high antioxidant potency, lower toxicity, but limited lipophilicity, as compared to MnTnHex-2-PyP5+. In this work we describe the experimental and computational studies that resulted in the development of the superb SOD mimic and redox modulator MnTnBuOE-2-PyP5+, whose remarkable biological activity has been recently described. Initially, MeO-containing analogues of the longer alkyl series were devised to increase biodistribution of the previously prepared MeOEt derivative and to reduce the toxicity of MnTnHex-2-PyP5+. The synthesis of four MeOalkyl derivatives (alkyl = Et, n-Bu, n-Pen, and n-Hex) were attempted for each ortho, meta, and para MnPs. An unexpected formation of methylated MnPs, whose relative distribution varied with the MeO-alkyl length and the MnP isomer, was observed (e.g., methylation was minimal in MeOEt samples and meta isomers, but was major in MeOPen and ortho cases). Such mixture had little effect on the MnIII/II redox couple and UV-vis spectral data, but greatly changed lipophilicity and in vivo efficacy. All attempts to prevent methylation were unsuccessful as revealed by TLC and ESI-MS data, and unwarranted reliable biological testing. Solvent, isomer, and isotopic labeled experiments showed that methylation originated from rearrangement of the MeO-moiety of the alkylating tosylate MeOalkylOTs. Two rearrangement mechanisms for MeO-derived methylation of the pyridyl moieties were studied through DFT methods using pyridine as a surrogate for the N-pyridylporphyrins. The direct methoxyalkylation mechanism was studied for comparison. All structures and energies have been obtained at both B3LYP/6-31G* and M06-2X/6-31G* levels in vaccum and/or DMF solvent at 105 oC. The solvent effect has been considered through the continuum CPCM model. All transition states and minima have been confirmed through frequency calculations. Preferential rearrangement pathways leading to methylation vs. methoxyalkylation were solvent-dependent and driven by the relative stability of the reaction intermediates and the corresponding cyclic ethers generated as co-products. Reactivity trends of the MeOalkylOTs systems given by DFT calculations in absence/presence of solvent correlated well with the experimental data. Overall, these studies pointed to the need to relocate O-atom closer to pyridyl moiety to optimize porphyrin properties, in agreement with MnTnBuOE-2-PyP5+ design and development.

Mn porphyrins; SOD mimics; Oxidative stress; Catalytic Antioxidants; Alkylation; Rearrangement

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