A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity.
Abstract
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+).
Type
Journal articleSubject
AnimalsMice, Inbred C57BL
Mice
Saccharomyces cerevisiae
Metalloporphyrins
Superoxide Dismutase
Spectrophotometry, Ultraviolet
Spectrometry, Mass, Electrospray Ionization
Molecular Mimicry
Oxidative Stress
Catalysis
Micelles
Male
Electrochemical Techniques
Permalink
https://hdl.handle.net/10161/23287Published Version (Please cite this version)
10.1016/j.freeradbiomed.2012.02.006Publication Info
Rajic, Zrinka; Tovmasyan, Artak; Spasojevic, Ivan; Sheng, Huaxin; Lu, Miaomiao; Li,
Alice M; ... Batinic-Haberle, Ines (2012). A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency
and lipophilicity with low toxicity. Free radical biology & medicine, 52(9). pp. 1828-1834. 10.1016/j.freeradbiomed.2012.02.006. Retrieved from https://hdl.handle.net/10161/23287.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Ines Batinic-Haberle
Professor Emeritus of Radiation Oncology
A major interest of mine has been in the design and synthesis of Mn porphyrin(MnP)-based
powerful catalytic antioxidants which helped establish structure-activity relationship
(SAR). It relates the redox property of metalloporphyrins to their ability to remove
superoxide. SAR has facilitated the design of redox-active therapeutics and served
as a tool for mechanistic considerations. Importantly SAR parallels the magnitu
Huaxin Sheng
Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries
in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma,
subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression
injury. We also established cardiac arrest and hemorrhagic shock models for studying
multiple organ dysfunction. Our current studies focus on two projects. One is to
examine the efficacy of catalytic antioxidant in treating cerebral is
Ivan Spasojevic
Associate Professor in Medicine
David Samuel Warner
Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including
ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection
Laboratories is dedicated to examining the pathophysiology of acute brain and spinal
cord injury with particular reference to disease states managed in the perioperative
or neurointensive care environments. Rodent recovery models of cerebral ischemia,
traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info