title: SOD therapeutics: latest insights into their structure-activity relationships and impact on the cellular redox-based signaling pathways.
abstract: CONCLUSIONS
  Superoxide dismutase (SOD) enzymes are indispensable and ubiquitous antioxidant defenses maintaining the steady-state levels of O2·(-); no wonder, thus, that their mimics are remarkably efficacious in essentially any animal model of oxidative stress injuries thus far explored.
  
  
  BACKGROUND
  Structure-activity relationship (half-wave reduction potential [E1/2] versus log kcat), originally reported for Mn porphyrins (MnPs), is valid for any other class of SOD mimics, as it is dominated by the superoxide reduction and oxidation potential. The biocompatible E1/2 of ∼+300 mV versus normal hydrogen electrode (NHE) allows powerful SOD mimics as mild oxidants and antioxidants (alike O2·(-)) to readily traffic electrons among reactive species and signaling proteins, serving as fine mediators of redox-based signaling pathways. Based on similar thermodynamics, both SOD enzymes and their mimics undergo similar reactions, however, due to vastly different sterics, with different rate constants.
  
  
  RESULTS
  Although log kcat(O2·(-)) is a good measure of therapeutic potential of SOD mimics, discussions of their in vivo mechanisms of actions remain mostly of speculative character. Most recently, the therapeutic and mechanistic relevance of oxidation of ascorbate and glutathionylation and oxidation of protein thiols by MnP-based SOD mimics and subsequent inactivation of nuclear factor κB has been substantiated in rescuing normal and killing cancer cells. Interaction of MnPs with thiols seems to be, at least in part, involved in up-regulation of endogenous antioxidative defenses, leading to the healing of diseased cells.
  
  
  CONCLUSIONS
  Mechanistic explorations of single and combined therapeutic strategies, along with studies of bioavailability and translational aspects, will comprise future work in optimizing redox-active drugs.
authors.affiliation: 1 Department of Radiation Oncology, Duke University Medical School , Durham, North Carolina.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.forename: Emily R H
authors.initials: ER
authors.lastname: Roberts
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018716:Molecular Mimicry; D010084:Oxidation-Reduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008665:Metalloporphyrins; D013482:Superoxide Dismutase