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Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins.

Publication ,  Journal Article
Tovmasyan, AG; Rajic, Z; Spasojevic, I; Reboucas, JS; Chen, X; Salvemini, D; Sheng, H; Warner, DS; Benov, L; Batinic-Haberle, I
Published in: Dalton Trans
April 28, 2011

Cationic Mn(III) N-alkylpyridylporphyrins (MnPs) are potent SOD mimics and peroxynitrite scavengers and diminish oxidative stress in a variety of animal models of central nervous system (CNS) injuries, cancer, radiation, diabetes, etc. Recently, properties other than antioxidant potency, such as lipophilicity, size, shape, and bulkiness, which influence the bioavailability and the toxicity of MnPs, have been addressed as they affect their in vivo efficacy and therapeutic utility. Porphyrin bearing longer alkyl substituents at pyridyl ring, MnTnHex-2-PyP(5+), is more lipophilic, thus more efficacious in vivo, particularly in CNS injuries, than the shorter alkyl-chained analog, MnTE-2-PyP(5+). Its enhanced lipophilicity allows it to accumulate in mitochondria (relative to cytosol) and to cross the blood-brain barrier to a much higher extent than MnTE-2-PyP(5+). Mn(III) N-alkylpyridylporphyrins of longer alkyl chains, however, bear micellar character, and when used at higher levels, become toxic. Recently we showed that meta isomers are ∼10-fold more lipophilic than ortho species, which enhances their cellular accumulation, and thus reportedly compensates for their somewhat inferior SOD-like activity. Herein, we modified the alkyl chains of the lipophilic meta compound, MnTnHex-3-PyP(5+) via introduction of a methoxy group, to diminish its toxicity (and/or enhance its efficacy), while maintaining high SOD-like activity and lipophilicity. We compared the lipophilic Mn(III) meso-tetrakis(N-(6'-methoxyhexyl)pyridinium-3-yl)porphyrin, MnTMOHex-3-PyP(5+), to a hydrophilic Mn(III) meso-tetrakis(N-(2'-methoxyethyl)pyridinium-3-yl)porphyrin, MnTMOE-3-PyP(5+). The compounds were characterized by uv-vis spectroscopy, mass spectrometry, elemental analysis, electrochemistry, and ability to dismute O(2)˙(-). Also, the lipophilicity was characterized by thin-layer chromatographic retention factor, R(f). The SOD-like activities and metal-centered reduction potentials for the Mn(III)P/Mn(II)P redox couple were similar-to-identical to those of N-alkylpyridyl analogs: log k(cat) = 6.78, and E(1/2) = +68 mV vs. NHE (MnTMOHex-3-PyP(5+)), and log k(cat) = 6.72, and E(1/2) = +64 mV vs. NHE (MnTMOE-3-PyP(5+)). The compounds were tested in a superoxide-specific in vivo model: aerobic growth of SOD-deficient E. coli, JI132. Both MnTMOHex-3-PyP(5+) and MnTMOE-3-PyP(5+) were more efficacious than their alkyl analogs. MnTMOE-3-PyP(5+) is further significantly more efficacious than the most explored compound in vivo, MnTE-2-PyP(5+). Such a beneficial effect of MnTMOE-3-PyP(5+) on diminished toxicity, improved efficacy and transport across the cell wall may originate from the favorable interplay of the size, length of pyridyl substituents, rotational flexibility (the ortho isomer, MnTE-2-PyP(5+), is more rigid, while MnTMOE-3-PyP(5+) is a more flexible meta isomer), bulkiness and presence of oxygen.

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Published In

Dalton Trans

DOI

EISSN

1477-9234

Publication Date

April 28, 2011

Volume

40

Issue

16

Start / End Page

4111 / 4121

Location

England

Related Subject Headings

  • Superoxide Dismutase
  • Oxidation-Reduction
  • Metalloporphyrins
  • Manganese
  • Isomerism
  • Inorganic & Nuclear Chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Escherichia coli
  • Electrochemistry
  • Biomimetic Materials
 

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Tovmasyan, A. G., Rajic, Z., Spasojevic, I., Reboucas, J. S., Chen, X., Salvemini, D., … Batinic-Haberle, I. (2011). Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins. Dalton Trans, 40(16), 4111–4121. https://doi.org/10.1039/c0dt01321h
Tovmasyan, Artak G., Zrinka Rajic, Ivan Spasojevic, Julio S. Reboucas, Xin Chen, Daniela Salvemini, Huaxin Sheng, David S. Warner, Ludmil Benov, and Ines Batinic-Haberle. “Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins.Dalton Trans 40, no. 16 (April 28, 2011): 4111–21. https://doi.org/10.1039/c0dt01321h.
Tovmasyan AG, Rajic Z, Spasojevic I, Reboucas JS, Chen X, Salvemini D, Sheng H, Warner DS, Benov L, Batinic-Haberle I. Methoxy-derivatization of alkyl chains increases the in vivo efficacy of cationic Mn porphyrins. Synthesis, characterization, SOD-like activity, and SOD-deficient E. coli study of meta Mn(III) N-methoxyalkylpyridylporphyrins. Dalton Trans. 2011 Apr 28;40(16):4111–4121.
Journal cover image

Published In

Dalton Trans

DOI

EISSN

1477-9234

Publication Date

April 28, 2011

Volume

40

Issue

16

Start / End Page

4111 / 4121

Location

England

Related Subject Headings

  • Superoxide Dismutase
  • Oxidation-Reduction
  • Metalloporphyrins
  • Manganese
  • Isomerism
  • Inorganic & Nuclear Chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Escherichia coli
  • Electrochemistry
  • Biomimetic Materials