biostudies-literatureAbuEid MNIGMS NIH HHS105670https://www.ebi.ac.uk/biostudies/studies/S-EPMC9768319biostudies-literatureUnknown25(12)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 (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toiScienceFluorinated triphenylphosphonium analogs improve cell selectivity and in vivo detection of mito-metformin.PMC9768319R35 GM128840McAllister DSmith BCKadamberi IPChaluvally-Raghavan PAbuEid MKeyes RFPeterson FSprague DJDwinell MBfalseFluorinated triphenylphosphonium analogs improve cell selectivity and in vivo detection of mito-metformin.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 (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity to2022-01-01T00:00:00Z2022 Dec2025-04-05T14:56:58.08Z2025-04-05T14:56:58.08ZS-EPMC97683193656771810.1016/j.isci.2022.105670