PSG6: A MITOCHONDRIALLY-TARGETED GENTISIC ACID DERIVATIVE EXERTS ANTIPLATELET ACTION VIA MITOCHONDRIAL COMPLEX I INHIBITION

Cardiovascular diseases are the leading cause of death worldwide, and cancer-associated thrombosis remains a major clinical challenge because of the interplay between tumour progression and platelet activation. Platelets contribute to thrombus formation by adhering to damaged endothelium and undergoing aggregation. Since mitochondria-targeted compounds are useful as antitumor and antiplatelet agents, we evaluated a series of triphenylphosphonium salts derived from gentisic acid alkyl esters with varying chain lengths, searching for antiplatelet agents with dual activity. The compound with a six-carbon chain (PSG6) exhibited the highest antiplatelet activity without increasing bleeding risk, whereas the cytotoxicity was found to increase with the chain length. PSG6 also showed selective anticancer effects, reducing tumor cell viability at micromolar concentrations, inducing mitochondrial fission, and lowering the mitochondrial membrane potential (ΔΨm) at 10 μM. Mechanistically, PSG6 decreased ΔΨm, inhibited the mitochondrial electron transport chain (ETC) at complex I, and increased intracellular calcium and reactive oxygen species (ROS) production. Complex I inhibition was confirmed in the yeast model organism Yarrowia lipolytica (IC 50 = 2.9 μM), and atomistic molecular dynamics simulations suggest that PSG6 may inhibit complex I by binding at the shallow site of the ∼30 Å long ubiquinone tunnel. These results position PSG6 as a promising mito-inhibitor candidate for antiplatelet therapy.