Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22-27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.

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The biological effects attributed to nitric oxide ( NO) and nitroxyl (HNO) have been extensively studied, propelling their array of putative clinical applications beyond cardiovascular disorders toward other age-related diseases, like cancer and neurodegenerative diseases. In this context, the unique properties and reactivity of the N-O bond enabled the development of several classes of compounds with potential clinical interest, among which NO and HNO donors, nitrones, and nitroxides are of particular importance. Although primarily studied for their application as cardioprotective agents and/or molecular probes for radical detection, continuous efforts have unveiled a wide range of pharmacological activities and, ultimately, therapeutic applications. These efforts are of particular significance for diseases in which oxidative stress plays a key pathogenic role, as shown by a growing volume of in vitro and in vivo preclinical data. Although in its early stages, these efforts may provide valuable guidelines for the development of new and effective N-O-based drugs for age-related disorders. In this report, we review recent advances in the chemistry of NO and HNO donors, nitrones, and nitroxides and discuss its pharmacological significance and potential therapeutic application.

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