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.
Abstract
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.
Type
Journal articleSubject
Escherichia coliManganese
Ascorbic Acid
Metalloporphyrins
Superoxide Dismutase
Oxidation-Reduction
Isomerism
Electrochemistry
Biomimetic Materials
Hydrophobic and Hydrophilic Interactions
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https://hdl.handle.net/10161/23289Published Version (Please cite this version)
10.1039/c0dt01321hPublication Info
Tovmasyan, Artak G; Rajic, Zrinka; Spasojevic, Ivan; Reboucas, Julio S; Chen, Xin;
Salvemini, Daniela; ... Batinic-Haberle, Ines (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 transactions (Cambridge, England : 2003), 40(16). pp. 4111-4121. 10.1039/c0dt01321h. Retrieved from https://hdl.handle.net/10161/23289.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.
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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
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