A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity.

Rajic, Zrinka

Tovmasyan, Artak

Spasojevic, Ivan

Sheng, Huaxin

Lu, Miaomiao

Li, Alice M

Gralla, Edith B

Warner, David S

Benov, Ludmil

Batinic-Haberle, Ines

2021-06-01T14:14:10Z

2021-06-01T14:14:10Z

2012-05

2021-06-01T14:14:10Z

The Mn porphyrins of k(cat)(O(2)(.-)) as high as that of a superoxide dismutase enzyme and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic the site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP(5+) is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP(5+) has been in part attributed to its micellar properties, i.e., the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH(2) group by an oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP(5+). The high SOD-like activity is preserved and even enhanced: log k(cat)(O(2)(.-))=7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP(5+) and MnTnHep-2-PyP(5+), respectively. MnTnBuOE-2-PyP(5+) was tested in an O(2)(.-) -specific in vivo assay, aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5-30 μM. MnTnHep-2-PyP(5+) was already toxic at 5 μM, and MnTnHex-2-PyP(5+) became toxic at 30 μM. In a mouse toxicity study, MnTnBuOE-2-PyP(5+) was several-fold less toxic than either MnTnHex-2-PyP(5+) or MnTnHep-2-PyP(5+).

S0891-5849(12)00083-4

0891-5849

1873-4596

https://hdl.handle.net/10161/23287

eng

Elsevier BV

Free radical biology & medicine

10.1016/j.freeradbiomed.2012.02.006

Animals

Mice, Inbred C57BL

Mice

Saccharomyces cerevisiae

Metalloporphyrins

Superoxide Dismutase

Spectrophotometry, Ultraviolet

Spectrometry, Mass, Electrospray Ionization

Molecular Mimicry

Oxidative Stress

Catalysis

Micelles

Male

Electrochemical Techniques

A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity.

Journal article

Spasojevic, Ivan|0000-0001-9890-6246

Sheng, Huaxin|0000-0002-4325-2940

1828

1834

9

School of Medicine

Neurobiology

Duke Institute for Brain Sciences

Surgery

Anesthesiology, Neuroanesthesia

Duke

Basic Science Departments

University Institutes and Centers

Institutes and Provost's Academic Units

Clinical Science Departments

Anesthesiology

Radiation Oncology

Duke Cancer Institute

Medicine, Medical Oncology

Institutes and Centers

Medicine

Published

52