Selective Delivery of Dicarboxylates to Mitochondria by Conjugation to a Lipophilic Cation via a Cleavable Linker

• DOI: 10.1021/acs.molpharmaceut.0c00533
• Publication Date: 2020-07-21T19:18:31Z
• Authors: Hiran A. Prag; Duvaraka Kula-Alwar; Laura Pala; Stuart T. Caldwell; Timothy E. Beach; Andrew M. James; Kourosh Saeb-Parsy; Thomas Krieg; Richard C. Hartley; Michael P. Murphy
• Keywords: Linker

Many mitochondrial metabolites and bioactive molecules contain two carboxylic acid moieties that make them unable to cross biological membranes. Hence, there is considerable interest in facilitating the uptake of these into cells mitochondria modify or report on their function. Conjugation triphenylphosphonium (TPP) lipophilic cation widely used deliver selectively response membrane potential. However, permanent attachment can disrupt function small dicarboxylates. Here, we have developed a strategy using TPP release dicarboxylates within mitochondria. For this, dicarboxylate attached compound via single ester bond, which then cleaved by intramitochondrial esterase activity, releasing organelle. Leaving second free also means dependent pH gradient across inner membrane. To assess this strategy, synthesized range monoesters model dicarboxylate, malonate. We tested accumulation ability malonate isolated cells, vitro vivo. A TPP-malonate monoester compound, TPP11-malonate, group was hydrophobic undecyl link, most effective at Therefore, TPP-monoester platform enables selective