Fluorinated triphenylphosphonium analogs improve cell selectivity and in vivo detection of mito-metformin

Abstract

Triphenylphosphonium (TPP + ) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP + -conjugated compounds. Here, we investigated the biological effects of direct modification to TPP + to improve the efficacy and detection of mito-metformin (MMe), a TPP + -conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs ( p CF 3 -MMe, m CF 3 -MMe, and p MeO-MMe) against multiple distinct human cancer cells. p CF 3 -MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining the same signaling mechanism. Importantly, p CF 3 -MMe allowed quantitative monitoring of cellular accumulation via 19 F-NMR in vitro and in vivo . Furthermore, adding trifluoromethyl groups to TPP + reduced toxicity in vivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP + -conjugated compounds.