A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin, combines superb potency and lipophilicity with low toxicity

• Published in: Free radical biology & medicine Vol. 52; no. 9; pp. 1828 - 1834
• Main Authors: Rajic, Zrinka, Tovmasyan, Artak, Spasojevic, Ivan, Sheng, Huaxin, Lu, Miaomiao, Li, Alice M., Gralla, Edith B., Warner, David S., Benov, Ludmil, Batinic-Haberle, Ines
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2012
• Subjects: aerobiosis; animal models; Animals; Catalysis; central nervous system diseases; Drug toxicity; Electrochemical Techniques; hydrophobicity; Male; manganese; Metalloporphyrins - pharmacology; Metalloporphyrins - toxicity; Mice; Mice, Inbred C57BL; Micelles; MnTnBuOE-2-PyP5; MnTnHex-2-PyP5; Molecular Mimicry; Oxidative Stress; oxygen; physical properties; porphyrins; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; SOD mimic; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; superoxide anion; superoxide dismutase; Superoxide Dismutase - metabolism; toxicity; yeasts; MnPs; MnTnBuOE-2-PyP5+ (BMX-001); O2; MnTnHex-2-PyP5; MnIIP and MnIIIP; NHE; kcat(O2.-); MnTnBuOE-2-PyP5; E1/2; SOD mimic; H2TnBuOE-2-PyP4; Rf; Drug toxicity; MnTnHep-2-PyP5; MnTMOHex-2-PyP5; HFBA; MnTnBuOE-3-PyP5; ip; SOD; MnTMOHex-3-PyP5; MnTnOct-2-PyP5; MnTnBu-2-PyP5; POW; MnTE-2-PyP5+ (AEOL10113, FBC007); MnTMOE-2-PyP5
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.02.006

The Mn porphyrins of kcat(O2.-) as high as that of a superoxide dismutase enzyme and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic the site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP5+ is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP5+ has been in part attributed to its micellar properties, i.e., the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH2 group by an oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+. The high SOD-like activity is preserved and even enhanced: log kcat(O2.-)=7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP5+ and MnTnHep-2-PyP5+, respectively. MnTnBuOE-2-PyP5+ was tested in an O2.- -specific in vivo assay, aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5–30μM. MnTnHep-2-PyP5+ was already toxic at 5μM, and MnTnHex-2-PyP5+ became toxic at 30μM. In a mouse toxicity study, MnTnBuOE-2-PyP5+ was several-fold less toxic than either MnTnHex-2-PyP5+ or MnTnHep-2-PyP5+. [Display omitted] ► Mn porphyrin-based SOD mimic, MnTnHex-2-PyP5+, was optimized to reduce its toxicity. ► Introduction of oxygen atoms into all 4 hexyl chains gave rise to the superb SOD mimic MnTnBuOE-2-PyP5+. ► Positioning of oxygen atoms deep within hexyl chains preserved the lipophilic character of MnTnHex-2-PyP5+. ► MnTnBuOE-2-PyP5+ is twice more potent SOD mimic, but few-fold less toxic, than MnTnHex-2-PyP5+.