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

Sofia BenfeitoCarlos FernandesDaniel ChavarriaSandra BarreiroFernando CagideLisa SequeiraJosé TeixeiraRenata SilvaFernando RemiaoPaulo J OliveiraEugenio UriarteFernanda Borges
Published in: Journal of medicinal chemistry (2023)
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.
Keyphrases
  • hydrogen peroxide
  • oxidative stress
  • reactive oxygen species
  • endothelial cells
  • nitric oxide
  • ionic liquid
  • cell death
  • signaling pathway
  • endoplasmic reticulum
  • big data
  • machine learning
  • amino acid