The design of redox active thiol peroxidase mimics: Dihydrolipoic acid recognition correlates with cytotoxicity and prooxidant action

Autor: Gregory I. Giles, B. Zadehvakili, S.M. McNeill, J.P. Fawcett
Rok vydání: 2016
Předmět:
Antioxidant
Cell Survival
medicine.medical_treatment
Cell Culture Techniques
01 natural sciences
Biochemistry
Redox
Catalysis
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Dihydrolipoic acid
Biomimetic Materials
Cell Line
Tumor
Organoselenium Compounds
Organometallic Compounds
medicine
Humans
Sulfhydryl Compounds
Electrodes
Pharmacology
chemistry.chemical_classification
Glutathione Peroxidase
Reactive oxygen species
Molecular Structure
biology
010405 organic chemistry
Glutathione peroxidase
Electrochemical Techniques
Hydrogen Peroxide
Glutathione
Oxidants
0104 chemical sciences
Solubility
chemistry
Drug Design
030220 oncology & carcinogenesis
biology.protein
Thiol
Tellurium
Hydrophobic and Hydrophilic Interactions
Oxidation-Reduction
Peroxidase
Zdroj: Biochemical Pharmacology. 104:19-28
ISSN: 0006-2952
Popis: 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 PhMC n H 2 n +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 ( k obs ) were then related to compound cytotoxicity and antioxidant versus prooxidant action in A549 cancer cells. The results show that the dihydrolipoic acid k obs values correlate with both cytotoxicity and prooxidant function. This enabled us to define a relationship, IC 50 = 10 + 280e −5(DHLA kobs ) , which allows the prediction of TPx mimic cytotoxicity. In contrast, hydrophobicity and glutathione k obs were unrelated to the compounds’ redox pharmacology.
Databáze: OpenAIRE
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