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

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)-O-center dot, CO3 center dot-, and (NO2)-N-center dot. Hence, 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 k(cat)(O-2(center dot-)) similar to the k(cat) of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP5+, MnTnHex-2-PyP5+, and MnTDE-2-ImP(5+). The ability to disproportionate O-2(center dot-) parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO-. The same structural feature that gives rise to the high k(cat)(O-2(center dot-)) and k(red)(ONOO-), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1 alpha, NF-kappa B, 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-ImP(5+) are potent in numerous animal models of diseases, the lipophilic analogues, such as MnTnHex-2-PyP5+, were developed to cross blood brain barrier and target central nervous system and critical cellular compartments, 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