Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics

Abstract

Oxidative stress, a redox imbalance between the endogenous reactive species and antioxidant systems, is common to numerous pathological conditions such as cancer, central nervous system injuries, radiation injury, diabetes etc. Therefore, compounds able to reduce oxidative stress have been actively sought for over 3 decades. Superoxide is the major species involved in oxidative stress either in its own right or through its progeny, such as ONOO−, H2O2, ·OH, CO3·−, and ·NO2. Therefore, the very first compounds developed in the late 1970-ies were the superoxide dismutase (SOD) mimics. Thus far the most potent mimics have been the cationic meso Mn(III) N-substituted pyridylporphyrins and N,N′-disubstituted imidazolylporphyrins (MnPs), some of them with kcat(O2·−) similar to the kcat of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP5+, MnTnHex-2-PyP5+, and MnTDE-2-ImP5+. The ability to disproportionate O2·− parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO−. The same structural feature that gives rise to the high kcat (O2·−) and kred (ONOO−), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1α, NF-κB, AP-1, and SP-1, and therefore modify the excessive inflammatory and immune responses. Coupling with cellular reductants and other redox-active endogenous proteins seems to be involved in the actions of Mn porphyrins. While hydrophilic analogues, such as MnTE-2-PyP5+ and MnTDE-2-ImP5+ are potent in numerous animal models of diseases, the lipophilic analogues were developed to cross blood brain barrier and target central nervous system and critical cellular compartment, mitochondria. The modification of its structure, aimed to preserve the SOD-like potency and lipophilicity, and diminish the toxicity, has presently been pursued. The pulmonary radioprotection by MnTnHex-2-PyP5+ was the first efficacy study performed successfully with non-human primates. The Phase I toxicity clinical trials were done on amyotrophic lateral sclerosis patients with N,N′-diethylimidazolium analogue, MnTDE-2-ImP5+ (AEOL10150). Its aggressive development as a wide spectrum radioprotector by Aeolus Pharmaceuticals has been supported by USA Federal government. The latest generation of compounds, bearing oxygens in pyridyl substituents is presently under aggressive development for cancer and CNS injuries at Duke University and is supported by Duke Translational Research Institute, The Wallace H. Coulter Translational Partners Grant Program, Preston Robert Tisch Brain Tumor Center at Duke, and National Institute of Allergy and Infectious Diseases. Metal center of cationic manganese porphyrins easily accepts and donates electrons as exemplified in the catalysis of O2·− dismutation. Thus such compounds may be equally good anti- and pro-oxidants; in either case the beneficial therapeutic effects may be observed. Moreover, while the in vivo effects may appear antioxidative, the mechanism of action of MnPs that produced such effects may be pro-oxidat...

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

“…Since all aerobic organisms inevitably generate superoxide, finding a suitable biosystem may appear easier than it actually is. Numerous articles report beneficial effects of SOD mimics in animal models of diseases and pathological conditions having oxidative stress as a common mechanism [for recent reviews, see (11,16,86,120)]. However, higher eukaryotic organism-based models are too complex, and biological activity of any studied agent depends on complicated pharmacokinetics, tissue gradient distribution, and others.…”

Neuroprotective Efficacy from a Lipophilic Redox-Modulating Mn(III) N-Hexylpyridylporphyrin, MnTnHex-2-PyP: Rodent Models of Ischemic Stroke and Subarachnoid Hemorrhage

“…The prevailing understanding is that MnPorphyrins remove signaling reactive species, which would otherwise activate transcription factors, thereby serving as antioxidants. An alternative and well justified scenario is that MnPorphyrins oxidize p50 or glutathionylate p65 subunits of NF-B (in the presence of glutathione and H 2 O 2 ), thereby acting as pro-oxidants (Tse et al, 2004;Batinić-Haberle et al, 2010b, 2011aJaramillo et al, 2010). These compounds have been evaluated in both mouse and rat models of middle cerebral artery occlusion (MCAO).…”

Mitochondria and Antioxidants: The Active Players in Islet Oxidative Stress

“…Manganese complexes of porphyrins were employed in studies of a number of biological models of oxidative stress (Batinic-Haberle et al 2011). In an animal model of STZ-diabetic rats, Mn-porphyrin MnTM-2-PyP 5+ , administered after the dose of STZ, counteracted the oxidative stress as judged by decreased levels of lipid peroxidation in blood plasma and erythrocytes (MDA products).…”