Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks

Although the lipophilic triphenylphosphonium (TPP+)
cation is widely used to target antioxidants to mitochondria, TPP+-based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2)
cells, decreasing intracellular adenosine triphosphate (ATP) levels,
leading to mitochondrial membrane depolarization and reduced mitochondrial
mass after 24 h. We surpassed this concern using nitrogen-derived
cationic carriers (Mito.PICO, Mito.ISOQ,
and Mito.IMIDZ). As opposed to Mito.TPP,
these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells
up to 50 μM and after 24 h of incubation. All of the cationic
derivatives accumulated inside the mitochondrial matrix and acted
as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed
that nitrogen-based cationic carriers can modulate the biological
performance of mitochondria-directed antioxidants and are an alternative
to the TPP cation.