Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models

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.