Neuroprotection by nature-inspired mitochondria-targeted phenolic derivatives

Neurological disorders (ND) are the leading cause of long-term disability and the second leading cause of death in the world. ND and related diseases have an impact on the sustainability of the national health and social system. The absence of resolutive therapies and in part to the poor efficacy of preventive measures represent the necessity to develop new therapies and interventions. Oxidative stress, together with aging and genetic factors, plays an important role in the occurrence of neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's diseases. Targeting drugs to subcellular compartments represents one of the modern trends in molecular pharmacology. Mitochondria are vital intracellular organelles and play a key role in energy production and regulation of cell-stress pathways. Unbalanced mitochondrial oxidative stress determine cell damage such as lipid peroxidation, protein oxidation, and DNA lesions. Mitochondria have some unique characteristics that can be used for targeting, but one of the limiting factors of antioxidant therapy in the treatment of mitochondrial diseases has been the inability to improve the levels of antioxidants in the mitochondria. In this context, a collection of mitochondria-targeted derivatives was designed and synthesized by covalently linking a lipophilic cation to some selected natural antioxidants (i.e., coumaric acid, sinapic acid, syringic acid, ferulic acid, gallic acid, caffeic acid and rosmarinic acid). The synthesis was optimized under flow conditions, using cyrene (i.e., dihydrolevoglucosenone) as the solvent. Cyrene is an eco-friendly bio-available solvent useful to replace dipolar aprotic solvents which are in the REACH restricted substances list. A two-step continuous flow protocol was developed, and the desired MITO-compounds were isolated in moderate to good yields. To evaluate the biological activity, the natural and MITO- derivatives were tested on in vitro neuronal SH-SY5Y cells. The spectroscopic characteristics of these compounds were analyzed and by MTS assay the IC50 was calculated. The neuroprotection activity was evaluated and, in order to investigate the effect on the mitochondrion, the JC-1 assay was performed under the neurodegenerative stimulus. The data obtained show that the MITO-derived compounds are more efficient to protect mitochondrion from oxidative stress.