15 research outputs found
Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential
Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia–reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO3·−, peroxyl radical, and less efficiently H2O2. By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877–918
Oxygen tension modulates the effects of TNF alpha in compressed chondrocytes
This work was supported by a QMUL Principal EPSRC PhD studentship and project grants by the AO Foundation (S-09-83C) and UM High Impact Research Grant (UM.C/HIR/MOHE/ENG/44) from the Ministry of Higher Education Malaysia
Rational Design of Superoxide Dismutase (SOD) Mimics: The Evaluation of the Therapeutic Potential of New Cationic Mn Porphyrins with Linear and Cyclic Substituents
Our
goal herein has been to gain further insight into the parameters which
control porphyrin therapeutic potential. Mn porphyrins (MnTnOct-2-PyP<sup>5+</sup>, MnTnHexOE-2-PyP<sup>5+</sup>, MnTE-2-PyPhP<sup>5+</sup>, and MnTPhE-2-PyP<sup>5+</sup>) that bear the same positive charge
and same number of carbon atoms at <i>meso</i> positions
of porphyrin core were explored. The carbon atoms of their <i>meso</i> substituents are organized to form either linear or
cyclic structures of vastly different redox properties, bulkiness,
and lipophilicities. These Mn porphyrins were compared to frequently
studied compounds, MnTE-2-PyP<sup>5+</sup>, MnTE-3-PyP<sup>5+</sup>, and MnTBAP<sup>3–</sup>. All MnÂ(III) porphyrins (MnPs) have
metal-centered reduction potential, <i>E</i><sub>1/2</sub> for Mn<sup>III</sup>P/Mn<sup>II</sup>P redox couple, ranging from
−194 to +340 mV versus NHE, log <i>k</i><sub>cat</sub>(O<sub>2</sub><sup>•–</sup>) from 3.16 to 7.92, and
log <i>k</i><sub>red</sub>(ONOO<sup>–</sup>) from
5.02 to 7.53. The lipophilicity, expressed as partition between n-octanol
and water, log <i>P</i><sub>OW</sub>, was in the range −1.67
to −7.67. The therapeutic potential of MnPs was assessed via:
(i) <i>in vitro</i> ability to prevent spontaneous lipid
peroxidation in rat brain homogenate as assessed by malondialdehyde
levels; (ii) <i>in vivo</i> O<sub>2</sub><sup>•–</sup> specific assay to measure the efficacy in protecting the aerobic
growth of SOD-deficient <i>Saccharomyces cerevisiae</i>;
and (iii) aqueous solution chemistry to measure the reactivity toward
major <i>in vivo</i> endogenous antioxidant, ascorbate.
Under the conditions of lipid peroxidation assay, the transport across
the cellular membranes, and in turn shape and size of molecule, played
no significant role. Those MnPs of <i>E</i><sub>1/2</sub> ∼ +300 mV were the most efficacious, significantly inhibiting
lipid peroxidation in 0.5–10 μM range. At up to 200 μM,
MnTBAP<sup>3–</sup> (<i>E</i><sub>1/2</sub> = −194
mV vs NHE) failed to inhibit lipid peroxidation, while MnTE-2-PyPhP<sup>5+</sup> with 129 mV more positive <i>E</i><sub>1/2</sub> (−65 mV vs NHE) was fully efficacious at 50 μM. The <i>E</i><sub>1/2</sub> of Mn<sup>III</sup>P/Mn<sup>II</sup>P redox
couple is proportional to the log <i>k</i><sub>cat</sub>(O<sub>2</sub><sup>•–</sup>), <i>i.e</i>.,
the SOD-like activity of MnPs. It is further proportional to <i>k</i><sub><i>r</i>ed</sub>(ONOO<sup>–</sup>) and the ability of MnPs to prevent lipid peroxidation. In turn,
the inhibition of lipid peroxidation by MnPs is also proportional
to their SOD-like activity. In an <i>in vivo S. cerevisiae</i> assay, however, while <i>E</i><sub>1/2</sub> predominates,
lipophilicity significantly affects the efficacy of MnPs. MnPs of
similar log <i>P</i><sub>OW</sub> and <i>E</i><sub>1/2</sub>, that have linear alkyl or alkoxyalkyl pyridyl substituents,
distribute more easily within a cell and in turn provide higher protection
to <i>S. cerevisiae</i> in comparison to MnP with bulky
cyclic substituents. The bell-shape curve, with MnTE-2-PyP<sup>5+</sup> exhibiting the highest ability to catalyze ascorbate oxidation,
has been established and discussed. Our data support the notion that
the SOD-like activity of MnPs parallels their therapeutic potential,
though species other than O<sub>2</sub><sup>•–</sup>, such as peroxynitrite, H<sub>2</sub>O<sub>2</sub>, lipid reactive
species, and cellular reductants, may be involved in their mode(s)
of action(s)