Substituted porphyrins

Abstract

To improve bioavailability of the catalytic metalloporphyrin-based SOD mimics Mn(III) 5,10,15,20-tetrakis[N-ethylpyridinium-2-yl]porphyrin (MnTE-2-PyP) and Mn(III) 5,10,15,20-tetrakis[N,N'-diethylimidazolium-2-yl]porphyrin (MnTDE-2-ImP), three new Mn(III) porphyrins, bearing oxygen atoms within side chains, were synthesized and characterized: Mn(III) 5,10,15,20-tetrakis[N-(2-methoxyethyl)pyridinium-2-yl]porphyrin (MnTMOE-2-PyP), Mn(III) 5,10,15,20-tetrakis[N-methyl-N′-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP) and Mn(III) 5,10,15,20-tetrakis[N,N′-di(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTDMOE-2-ImP). The catalytic rate constants for Odismutation (and the related metal-centered redox potentials vs NHE) for the new compounds are: log k=8.04 (E=+251 mV) for MnTMOE-2-PyP, log k.=7.98 (E=+356 mV) for MnTM,MOE-2-ImPand log k=7.59 (E=+365 mV) for MnTDMOE-2-ImP. At 30 μM levels none of the new compounds were toxic, and allowed SOD-deficientto grow nearly as well as wild type. At 3 μM levels, the MnTDMOE-2-ImP, bearing an oxygen atom within each of the eight side chains, was the most effective and offered much higher protection than MnTE-2-PyP, while MnTDE-2-ImPwas inefficient. These new porphyrins were compared to Mn(III) N-alkylpyridylporphyrins. While longer-chain n-alkyl members of the series exerted toxicity at higher concentration levels, they were very effective at submicromolar levels. Thus, 0.3 μM Mn(III) tetrakis(N-n-hexyl-pyridinum-2-yl)porphyrin and its n-octyl analogue offered the same level of protection as did >10 μM methyl and ethyl porphyrins. The kof methyl and n-octyl porphyrins are identical, but n-octyl is −10-fold more lipophilic. Therefore, the 30-fold improvement in bioavailability appears to be due to the increase in lipophilicity. MnTDMOE-2-ImPand longer-chain Mn(III) N-alkylpyridylporphyrins may offer better treatment for oxidative stress injuries than the previously studied MnTE-2-PyPand MnTDE-2-ImP.