Catalytic antioxidant therapy by metallodrugs: lessons from metallocorroles.

SIGNIFICANCE: the fundamental science behind the "antioxidant therapy", i.e., the importance of eliminating oxidizing species that may damage vital biomolecules and induce biological malfunctions, is well established. Nevertheless, quite disappointing results were reported in several recent meta-analyses that addressed the effects of vitamins and other antioxidant supplements on the many diseases that are associated with oxidative events. This emphasizes the importance of elucidating factors that might be responsible for the large gap between the hypothesis and practice. RECENT ADVANCES: classical "antioxidant therapy" deals with stoichiometric antioxidants whose role is sacrificial, i.e., they are consumed on a one-to-one basis by being oxidized instead of vital biomolecules. On the other hand, catalytic antioxidants detoxify the reactive species without being permanently oxidized, and one molecule may hence disarm numerous oxidants. The benefits of catalytic antioxidants in pure chemical systems and in animal models of many diseases are quite established and have been summarized in several reviews. CRITICAL ISSUES: the main aim of this article is to provide a perspective on the utility of metal-based catalytic antioxidants, with a focus on those chelated by corroles, for disease prevention or treatment. Particular emphasis is on the often-ignored fact that redox-based therapeutics is potentially harmful because it may actually induce rather than decrease oxidative stress. FUTURE DIRECTIONS: investigations aimed at identifying the factors that increase the antioxidant versus pro-oxidant potency of synthetic metal complexes are crucial for the optimal design of redox-based drug candidates that may be used for combating the numerous diseases that are affected by oxidative stress.