High Lipophilicity of meta Mn(III) <i>N</i>-Alkylpyridylporphyrin-Based Superoxide Dismutase Mimics Compensates for Their Lower Antioxidant Potency and Makes Them as Effective as Ortho Analogues in Protecting Superoxide Dismutase-Deficient <i>Escherichia coli</i>

Kos, Ivan; Benov, Ludmil; Spasojević, Ivan; Rebouças, Júlio S.; Batinić‐Haberle, Ines

doi:10.1021/jm900576g

Cited by 57 publications

(80 citation statements)

References 32 publications

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“…Assessment of partitioning between n-octanol and water revealed that each additional carbon atom added to the N-alkyl chains increases lipophilicity by 10-fold. An additional 10-fold increase of lipophilicity can be achieved by moving the N-alkyl groups from the ortho to meta N-pyridyl position (29). Here we demonstrate that a 50-fold increase in the lipophilicity of Zn N-alkylpyridylporphyrins produced by lengthening the side chains from 1 (methyl) to 6 carbons (hexyl), caused ϳ5-fold increase in the uptake of the PS by the cancer cells.…”

Section: Discussionmentioning

confidence: 63%

“…Uptake and subcellular localization of PSs in turn are controlled mainly by the net charge and lipophilicity of the molecule (22). Studies on photo-insensitive MnP analogs have shown that desired lipophilicity can be achieved by adding suitable alkyl substituents at the meso pyridyl positions, without affecting the net positive charge of the molecule (23,29). Assessment of partitioning between n-octanol and water revealed that each additional carbon atom added to the N-alkyl chains increases lipophilicity by 10-fold.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins

Ezzeddine¹,

Al-Banaw

Tovmasyan

et al. 2013

Journal of Biological Chemistry

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Background: Delivering molecules to selected cellular compartments is important for analytical and practical purposes. Results: Varying the length and positions of alkyl substituents results in preferential uptake of zinc porphyrins by particular cellular structures. Conclusion: Uptake, distribution, and phototoxicity of porphyrins depend on charge, lipophilicity, and molecular shape. Significance: Systematic chemical modification provides the basis for rational design of molecules targeting specific cellular compartments.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins

Ezzeddine¹,

Al-Banaw

Tovmasyan

et al. 2013

Journal of Biological Chemistry

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“…Higher lipophilicity of meta Mn(III) N-alkylpyridylporphyrins drives their higher accumulation inside E. coli and compensates for lower antioxidant potency when compared with ortho analogues. Consequently, meta and ortho isomers are similarly efficacious in protecting SOD-deficient E. coli that lacks cytosolic SOD (178). Here, the most obvious case with ortho and meta N-ethylpyridylporpyrin is illustrated: meta isomer is~10-fold less SOD-active than the ortho species, but is 10-fold more lipophilic and accumulates~10-fold more in E. coli.…”

Section: K Other Modes Of Actionmentioning

confidence: 93%

“…Although the first evidence of their in vivo effects was published in J Biol Chem 1998 (29), meta isomers have been overlooked for decade. They are 3.6-to 15-fold less-potent SOD mimics, but are 10-fold more lipophilic and accumulate more in E. coli than ortho analogues (Table 1) (178). Figure 7 depicts the most obvious case; meta MnTE-3-PyP 5þ is an *10-fold less potent SOD mimic but is *10-fold more lipophilic than MnTE-2-PyP 5þ .…”

Section: E Bioavailability Of Mn Porphyrinsmentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

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470

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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“…Uptake of cationic metalloporphyrins by E. coli and mitochondria of eukaryotic cells is driven by the electrochemical proton gradient across membranes and is facilitated by the amphiphilic properties of the molecule. Depending on the alkyl chain length, MnPs accumulate more in membranes or in cytosol; the longer alkyl-chain analogs tend to accumulate more in membranes than in cytosol (66).…”

Section: The Accumulation Of Mnps By E Coli and S Cerevisiaementioning

confidence: 99%

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Tovmasyan

Rebouças

Benov

2014

Antioxidants & Redox Signaling

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Significance: Half a century of research provided unambiguous proof that superoxide and species derived from it-reactive oxygen species (ROS)-play a central role in many diseases and degenerative processes. This stimulated the search for pharmaceutical agents that are capable of preventing oxidative damage, and methods of assessing their therapeutic potential. Recent Advances: The limitations of superoxide dismutase (SOD) as a therapeutic tool directed attention to small molecules, SOD mimics, that are capable of catalytically scavenging superoxide. Several groups of compounds, based on either metal complexes, including metalloporphyrins, metallocorroles, Mn(II) cyclic polyamines, and Mn(III) salen derivatives, or non-metal based compounds, such as fullerenes, nitrones, and nitroxides, have been developed and studied in vitro and in vivo. Very few entered clinical trials. Critical Issues and Future Directions: Development of SOD mimics requires in-depth understanding of their mechanisms of biological action. Elucidation of both molecular features, essential for efficient ROS-scavenging in vivo, and factors limiting the potential side effects requires biologically relevant and, at the same time, relatively simple testing systems. This review discuses the advantages and limitations of genetically engineered SOD-deficient unicellular organisms, Escherichia coli and Saccharomyces cerevisiae as tools for investigating the efficacy and mechanisms of biological actions of SOD mimics. These simple systems allow the scrutiny of the minimal requirements for a functional SOD mimic: the association of a high catalytic activity for superoxide dismutation, low toxicity, and an efficient cellular uptake/biodistribution. Antioxid. Redox Signal. 20, 2416Signal. 20, -2436

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High Lipophilicity of meta Mn(III) N-Alkylpyridylporphyrin-Based Superoxide Dismutase Mimics Compensates for Their Lower Antioxidant Potency and Makes Them as Effective as Ortho Analogues in Protecting Superoxide Dismutase-Deficient Escherichia coli

Cited by 57 publications

References 32 publications

Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins

Effect of Molecular Characteristics on Cellular Uptake, Subcellular Localization, and Phototoxicity of Zn(II) N-Alkylpyridylporphyrins

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

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