The mitochondrion’s negatively charged membrane potential has been well documented to drive the accumulation
of membrane permeable delocalized lipophilic cations (DLC). DLC attachments to known bioactive compounds
can direct organelle localization and improve drug exposure to targets within the mitochondria. Due to the mitochondria’s
essential function and its regulation of cell death, DLC targeted therapies are the focus of drug discovery
projects altering cellular fate via mitochondrial targets. This review provides an update on recent developments for the
two main applications of DLCs: cytoprotective therapies aimed at reducing oxidative stress and cytotoxic therapies
aimed at initiating cell death for the treatment of various cancers. Both approaches have produced significant improvements
using DLC conjugated compounds that include improved potency, pharmacokinetic properties, and the potential
to overcome resistance mechanisms.
Keywords: Anticancer, Cytotoxicity, Delocalized lipophilic cations, Mitochondria-targeted delivery, Oxidative stress, Smallmolecule
drug design, Triphenylphosphonium.
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