Duke University

Ivan Spasojevic

Ines Batinic-Haberle

Irwin Fridovich

Susan M Ludeman

Michael O Colvin

Michael P Gamcsik

Artak Tovmasyan

Provided herein are fluoro-substituted porphyrin compounds, such as those having a structure represented by Formula (I), wherein Ris a C1-C8 alkyl that is substituted with at least 1 fluorine (e.g., a C1-C8 alkyl substituted with 1-17 fluorine atoms); and X is an anion (e.g. a halogen ion (e.g., chloride, etc.), PF, tosylate, besylate, and/or mesylate). Also provided herein are methods of making the fluoro-substituted porphyrin compounds, pharmaceutical formulations containing the same, and methods of use thereof.

Fluoro substituted porphyrin compounds, pharmaceutical compositions comprising the same, and methods of preparing and using the same

Substituted metalloporphyrin compounds are described, along with pharmaceutical compositions containing the same, and methods of use thereof in protecting cells from oxidant-induced toxicity and pathological conditions such as inflammatory lung disease, neurodegenerative conditions, radiation injury, cancer, diabetes, cardiac conditions and sickle cell disease. Mn(III) porphyrins bearing oxygen atoms within side chains are particularly described.

Substituted porphyrins

The present invention provides a method of hydroxylating or oxidizing a compound of interest in a subject (e.g., a cytotoxic oxazaphosphorine prodrug), by administering the compound of interest to the subject; and concurrently administering the subject a metalloporphyrin in an amount effective to hydroxylate or oxidize the compound of interest in the subject.

Method of activation of oxazaphosphorines

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&#x2032;-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP) and Mn(III) 5,10,15,20-tetrakis[N,N&#x2032;-di(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTDMOE-2-ImP). The catalytic rate constants for O.dismutation (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 &#x3bc;M levels none of the new compounds were toxic, and allowed SOD-deficientto grow nearly as well as wild type. At 3 &#x3bc;M 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 &#x3bc;M Mn(III) tetrakis(N-n-hexyl-pyridinum-2-yl)porphyrin and its n-octyl analogue offered the same level of protection as did &#x2267;10 &#x3bc;M methyl and ethyl porphyrins. The kof methyl and n-octyl porphyrins are identical, but n-octyl is &#x2dc;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.

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&#x2032;-(2-methoxyethyl)imidazolium-2-yl]porphyrin (MnTM,MOE-2-ImP) and Mn(III) 5,10,15,20-tetrakis[N,N&#x2032;-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 &#x3bc;M levels none of the new compounds were toxic, and allowed SOD-deficientto grow nearly as well as wild type. At 3 &#x3bc;M 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 &#x3bc;M Mn(III) tetrakis(N-n-hexyl-pyridinum-2-yl)porphyrin and its n-octyl analogue offered the same level of protection as did &#x3e;10 &#x3bc;M methyl and ethyl porphyrins. The kof methyl and n-octyl porphyrins are identical, but n-octyl is &#x2212;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. 

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, R; (b) metal-entered redox potential, Efrom +220 to +367 mV vs NHE, and (c) proton dissociation constant, pKfrom 10.9 to 13.2. A linear correlation was found between Eand Rof the Mn(III) porphyrins and between the pKand Rof 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 Eincreases linearly with the increase in pK, 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 Ewith the increase in chain length, the catalytic rate constant decreases from methyl (log k=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.

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Durham, NC, United States of America

Ivan Spasojevic