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31 条记录 (耗时 0.036 秒)

    Substituted Porphyrins
    13.
    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+.

    Substituted porphyrins
    14.
    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
    17.
    发明授权
    Substituted porphyrins 有权
    取代卟啉

    公开(公告)号：US07485721B2

    公开(公告)日：2009-02-03

    申请号：US10456956

    申请日：2003-06-09

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

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

    IPC分类号： C07B47/00 ,  C07D487/22

    CPC分类号： C07D487/22

    摘要： A series of ortho isomers of meso tetrakis N-alkylpyridylporphyrins (alkyl being methyl, ethyl, n-propyl, n-butyl, n-hexyl, and n-octyl) and their Mn(III) complexes were synthesized and characterized by elemental analysis, uv/vis spectroscopy, electrospray ionization mass spectrometry and electrochemistry. An increase in the number of carbon atoms in the alkyl chains from 1 to 8 is accompanied by an increase in: (a) lipophilicity measured by the chromatographic retention factor, Rf; (b) metal-entered redox potential, E1/2 from +220 to +367 mV vs NHE, and (c) proton dissociation constant, pKa2 from 10.9 to 13.2. A linear correlation was found between E1/2 and Rf of the Mn(III) porphyrins and between the pKa2 and Rf of the metal-free compounds. As the porphyrins become increasingly more lipophilic, the decrease in hydration disfavors the separation of charges, while enhancing the electron-withdrawing effect of the positively charged pyridyl nitrogen atoms. Consequently, the E1/2 increases linearly with the increase in pKa2, a trend in porphyrin basicity opposite from the one we previously reported for other water-soluble Mn(III) porphyrins. All of these Mn(III) porphyrins are potent catalysts for superoxide dismutation (disproportionation). Despite the favorable increase of E1/2 with the increase in chain length, the catalytic rate constant decreases from methyl (log kcat=7.79) to n-butyl, and then increases such that the n-octyl is as potent an SOD mimic as are the methyl and ethyl compounds. The observed behavior originates from an interplay of hydration and steric effects that modulate electronic effects.

    摘要翻译： 通过元素分析合成了一系列内消旋四烷基吡啶基卟啉（烷基为甲基，乙基，正丙基，正丁基，正己基和正辛基）的邻位异构体及其Mn（III）络合物， 紫外/可见光谱，电喷雾离子化质谱和电化学。 烷基链中碳原子数1〜8的增加伴随着：（a）通过色谱保留因子Rf测定的亲油性; （b）金属进入的氧化还原电位，E1 / 2从+220到+367mV对NHE，和（c）质子解离常数，pKa2从10.9到13.2。 在Mn（III）卟啉的E1 / 2和Rf之间以及无金属化合物的pKa2和Rf之间发现线性相关。 当卟啉变得越来越亲油时，水合的减少不利于电荷的分离，同时增强带正电的吡啶基氮原子的吸电子效应。 因此，E1 / 2随着pKa2的增加而线性增加，卟啉碱度与之前报道的其他水溶性Mn（III）卟啉相反。 所有这些Mn（III）卟啉是超氧化物歧化（歧化）的有效催化剂。 尽管随着链长的增加E1 / 2有所增加，但催化速率常数从甲基（log kcat = 7.79）下降到正丁基，然后增加，使正辛基与SOD模拟物一样有效 甲基和乙基化合物。 观察到的行为源于调节电子效应的水合和空间效应的相互作用。