Stability of Phenyl-Modified Triphenylphosphonium Conjugates and Interactions with DTPA

Abstract

Triphenylphosphonium (TPP+) conjugates are effective in targeting drugs and probes to the mitochondria due to their lipophilic character that allows them to readily cross membranes and their large cationic radius that enables mitochondrial uptake because of the mitochondria’s negative membrane potential. TPP+ conjugates, while effectively sequestered by the mitochondria, are also known to uncouple oxidative phosphorylation (OXPHOS) and depolarize the mitochondrial membrane. xTPP+ conjugates with para-substitutions of functional groups on the phenyl rings of the TPP+ moiety display different levels of dose-mediated cytotoxicity due to differing potencies of uncoupling. xTPP+ conjugates having a para CF3 group substituted on the phenyl rings have been shown to afford significantly reduced uncoupling potency. In the present study, the analysis of a CF3-TPP+ conjugate with a decyl linker for stability revealed instability specific to the presence of DMSO in aqueous alkaline buffer. It is also demonstrated that the metal chelator, DTPA, forms a noncovalent protective complex with TPP+ moieties and prevents degradation of the CF3-TPP+ conjugate in aqueous DMSO. The stability of different xTPP+ conjugates and their interactions with DTPA are reported.