title: The design of redox active thiol peroxidase mimics: Dihydrolipoic acid recognition correlates with cytotoxicity and prooxidant action.
abstract: Redox active molecules containing organoselenium or organotellurium groups catalyse the oxidation of cellular thiols by hydrogen peroxide and are currently being developed as therapeutic agents. Potentially these synthetic thiol peroxidase (TPx) mimics can protect cells from oxidative stress by catalysing the reduction of reactive oxygen species by the cellular thiol glutathione, an activity which mimics the function of the antioxidant enzyme glutathione peroxidase. Alternatively they can act as prooxidants by catalysing the oxidation of essential thiol species within the cell. However the structure-activity relationships which determine the choice of thiol substrate, and hence the overall antioxidant or prooxidant outcome of drug administration, remain unknown. We report the first study that relates the pharmacological properties of TPx mimics with their solubility and catalytic activity using different thiol substrates. We used a series of structurally related compounds PhMCnH2n+1 (M=Se, Te; n=4-7) and investigated their ability to catalyse the oxidation of the cellular thiols glutathione and dihydrolipoic acid by hydrogen peroxide. The resulting rate constants (kobs) were then related to compound cytotoxicity and antioxidant versus prooxidant action in A549 cancer cells. The results show that the dihydrolipoic acid kobs values correlate with both cytotoxicity and prooxidant function. This enabled us to define a relationship, IC50=10+280e(-5(DHLA) (kobs)), which allows the prediction of TPx mimic cytotoxicity. In contrast, hydrophobicity and glutathione kobs were unrelated to the compounds' redox pharmacology.
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: B
authors.initials: B
authors.lastname: Zadehvakili
authors.affiliation: Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: S M
authors.initials: SM
authors.lastname: McNeill
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: J P
authors.initials: JP
authors.lastname: Fawcett
authors.affiliation: Department of Pharmacology and Toxicology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand. Electronic address: gregory.giles@otago.ac.nz.
authors.forename: G I
authors.initials: GI
authors.lastname: Giles
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D055664:Electrochemical Techniques; D004566:Electrodes; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000737:chemistry / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D012995:Solubility; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013691:Tellurium / Q000737:chemistry
chemical_list: D009942:Organometallic Compounds; D016566:Organoselenium Compounds; D016877:Oxidants; D013438:Sulfhydryl Compounds; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D013691:Tellurium
keywords: Dihydrolipoic acid; Drug design; Glutathione peroxidase; Organoselenium; Organotellurium; Redox