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

Autori
Batinić-Haberle, Ines ; Rajić, Zrinka ; Tovmasyan, Artak ; Reboucas, Julio S. ; Ye, Xiaodong ; Leong, Kam W. ; Dewhirst, Mark W. ; Vujašković, Željko ; Benov, Ludmil ; Spasojević, Ivan

Izvornik
Free radical biology & medicine (0891-5849) 51 (2011), 5; 1035-1053

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Mn porphyrins; SOD mimics; peroxynitrite scavengers; pro-oxidants; antioxidants; oxidative stress; reactive species; MnTE-2-PyP5+; MnTnHex-2-PyP5+; MnTDE-2-ImP5+; AEOL10150; AEOL10113

Sažetak
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-1a, NF-kB, 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 prooxidative ; the most obvious example being the inhibition of NF- erefore teach us that we need to distinguish between the mechanism/s of action/s of MnPs and the effects we observe. A number of factors impact the type of action of MnPs leading to favorable therapeutic effects: levels of reactive species and oxygen, levels of endogenous antioxidants (enzymes and low-molecular compounds), levels of MnPs, their site of accumulation, and the mutual encounters of all of those species. The complexity of in vivo redox systems and the complex redox chemistry of MnPs challenge and motivate us to further our understanding of the physiology of the normal and diseased cell with ultimate goal to successfully treat human diseases.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA