Study of the effects of phenolic acids and their triphenylphosphonium derivatives on the permeability and state of liposomal membrane, the functional activity of isolated rat liver mitochondria, and the survival of MCF-7 cells

Abstract

This study shows the effects of phenolic acids (gallic, coumaric, caffeic, and ferulic) and their triphenylphosphonium (TPP⁺) derivatives on the state of liposomal membrane, the functioning of isolated rat liver mitochondria, and the survival of MCF-7 breast adenocarcinoma cells. It was demonstrated that alkyltriphenylphosphonium esters of phenolic acids in contrast to their parental compounds, increase liposome membrane permeability to sulforhodamine B without altering their phase state. These derivatives also exhibit uncoupling effects on oxidative phosphorylation, reducing membrane potential and stimulating oxygen consumption in mitochondria fueled by glutamate/malate (substrate for complex I of the respiratory chain) or succinate (substrate for complex II). In addition, the compounds reduced the ability of mitochondria to uptake and retain Ca²⁺, suggesting their influence on calcium homeostasis. Conjugation of phenolic acids with the TPP⁺ moiety significantly enhanced their cytotoxic effects on MCF-7 cells. This study establishes a clear structure-activity relationship, demonstrating that conjugation with TPP⁺ via an ester linker is an advantageous strategy for enhancing the mitochondrial targeting and bioactivity of phenolic acids compared to amide linkage or the parental compounds.