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    Substituted porphyrins
    2.
    发明授权
    Substituted porphyrins 有权

    公开(公告)号：US07807825B2

    公开(公告)日：2010-10-05

    申请号：US10588332

    申请日：2005-02-01

    申请人： Ines Batinic-Haberle ,  Irwin Fridovich ,  Ivan Spasojevic

    发明人： Ines Batinic-Haberle ,  Irwin Fridovich ,  Ivan Spasojevic

    IPC分类号： C07B47/00 ,  C07D487/22

    CPC分类号： C07F13/005 ,  C07D401/14 ,  C07D403/14 ,  C07D487/22

    摘要： To improve bioavailability of the catalytic metalloporphyrin-based SOD mimics Mn(III) 5,10,15,20-tetrakis[N-ethylpyridinium-2-yl]porphyrin (MnTE-2-PyP5+) and Mn(III) 5,10,15,20-tetrakis[N,N′-diethylimidazolium-2-yl]porphyrin (MnTDE-2-ImP5+), 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-PyP5+), Mn(III) 5,10,15,20-tetrakis[N-methyl-N′-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP5+) and Mn(III) 5,10,15,20-tetrakis[N,N′-di(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTDMOE-2-ImP5+). The catalytic rate constants for O2 dismutation (and the related metal-centered redox potentials vs NHE) for the new compounds are: log kcat=8.04 (E1/2=+251 mV) for MnTMOE-2-PyP5+, log k.cat=7.98 (E1/2=+356 mV) for MnTM,MOE-2-ImP5+ and log kcat=7.59 (E1/2=+365 mV) for MnTDMOE-2-ImP5+. At 30 μM levels none of the new compounds were toxic, and allowed SOD-deficient E. coli to grow nearly as well as wild type. At 3 μM levels, the MnTDMOE-2-ImP5+, bearing an oxygen atom within each of the eight side chains, was the most effective and offered much higher protection than MnTE-2-PyP5+, while MnTDE-2-ImP5+ was 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 kcat of 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-ImP5+ and longer-chain Mn(III) N-alkylpyridylporphyrins may offer better treatment for oxidative stress injuries than the previously studied MnTE-2-PyP5+ and MnTDE-2-ImP5+.

    Substituted Porphyrins
    5.
    发明申请
    Substituted Porphyrins 有权

    公开(公告)号：US20080021007A1

    公开(公告)日：2008-01-24

    申请号：US10588332

    申请日：2005-02-01

    申请人： Ines Batinic-Haberle ,  Irwin Fridovich ,  Ivan Spasojevic

    发明人： Ines Batinic-Haberle ,  Irwin Fridovich ,  Ivan Spasojevic

    IPC分类号： A61K39/395 ,  A61P25/00 ,  A61P35/00 ,  A61P43/00 ,  A61P5/00 ,  A61P9/00 ,  C07D487/22 ,  C12N1/20 ,  C12N5/06

    CPC分类号： C07F13/005 ,  C07D401/14 ,  C07D403/14 ,  C07D487/22

    摘要： To improve bioavailability of the catalytic metalloporphyrin-based SOD mimics Mn(III) 5,10,15,20-tetrakis[N-ethylpyridinium-2-yl]porphyrin (MnTE-2-PyP5+) and Mn(III) 5,10,15,20-tetrakis[N,N′-diethylimidazolium-2-yl]porphyrin (MnTDE-2-ImP5+), 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-PyP5+), Mn(III) 5,10,15,20-tetrakis[N-methyl-N′-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP5+) and Mn(III) 5,10,15,20-tetrakis[N,N′-di(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTDMOE-2-ImP5+). The catalytic rate constants for O2 dismutation (and the related metal-centered redox potentials vs NHE) for the new compounds are: log kcat=8.04 (E½=+251 mV) for MnTMOE-2-PyP5+, log kcat=7.98 (E½=+356 mV) for MnTM,MOE-2-ImP5+ and log kcat=7.59 (E½=+365 mV) for MnTDMOE-2-ImP5+. At 30 μM levels none of the new compounds were toxic, and allowed SOD-deficient E. coli to grow nearly as well as wild type. At 3 μM levels, the MnTDMOE-2-ImP5+, bearing an oxygen atom within each of the eight side chains, was the most effective and offered much higher protection than MnTE-2-PyP5+, while MnTDE-2-ImP5+ was 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 kcat of 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-ImP5+ and longer-chain Mn(III) N-alkylpyridylporphyrins may offer better treatment for oxidative stress injuries than the previously studied MnTE-2-PyP5+ and MnTDE-2-ImP5+.