Design, mechanism of action, bioavailability and therapeutic effects of mn porphyrin-based redox modulators.
Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log k(cat)O2-*), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP5+, MnTDE-2-ImP5+, MnTnHex-2-PyP5+ and MnTnBuOE-2-PyP5+, are under preclinical and clinical development.
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Artak
A
Tovmasyan
Huaxin
H
Sheng
Tin
T
Weitner
Amanda
A
Arulpragasam
Miaomiao
M
Lu
David S
DS
Warner
Zeljko
Z
Vujaskovic
Ivan
I
Spasojevic
Ines
I
Batinic-Haberle
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002493:Central Nervous System Diseases / Q000188:drug therapy; D003287:Contrast Media / Q000737:chemistry; D003920:Diabetes Mellitus / Q000188:drug therapy; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000494:pharmacology
D003287:Contrast Media; D016166:Free Radical Scavengers; D011166:Porphyrins; D008345:Manganese; D013482:Superoxide Dismutase