Selective Delivery of Dicarboxylates to Mitochondria by Conjugation to a Lipophilic Cation via a Cleavable Linker
| Autor: | Stuart T. Caldwell, Duvaraka Kula-Alwar, Richard C. Hartley, Michael P. Murphy, Timothy E. Beach, Kourosh Saeb-Parsy, Laura Pala, Andrew M. James, Hiran A. Prag, Thomas Krieg |
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| Přispěvatelé: | Prag, Hiran [0000-0002-4753-8567], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Krieg, Thomas [0000-0002-5192-580X], Murphy, Mike [0000-0003-1115-9618], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
Male
esterase Carboxylic acid Carboxylic Acids Pharmaceutical Science 02 engineering and technology Mitochondrion 030226 pharmacology & pharmacy Article Membrane Potentials 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Drug Delivery Systems Organophosphorus Compounds Heterocyclic Compounds Cations Cell Line Tumor Drug Discovery Organelle Inner membrane Animals Humans Rats Wistar lipophilic cation chemistry.chemical_classification Membrane potential Cell Membrane Biological membrane Esters dicarboxylate delivery mitochondriatargeting 021001 nanoscience & nanotechnology Combinatorial chemistry In vitro Malonates Rats Mice Inbred C57BL mitochondria Malonate chemistry Molecular Medicine Female 0210 nano-technology Hydrophobic and Hydrophilic Interactions HeLa Cells |
| Zdroj: | Molecular Pharmaceutics |
| ISSN: | 1543-8384 |
| Popis: | 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 molecules into cells and mitochondria to modify or report on their function. Conjugation to the triphenylphosphonium (TPP) lipophilic cation is widely used to deliver molecules selectively to mitochondria in response to the membrane potential. However, permanent attachment to the cation can disrupt the biological function of small dicarboxylates. Here, we have developed a strategy using TPP to release dicarboxylates selectively within mitochondria. For this, the dicarboxylate is attached to a TPP compound via a single ester bond, which is then cleaved by intramitochondrial esterase activity, releasing the dicarboxylate within the organelle. Leaving the second carboxylic acid free also means mitochondrial uptake is dependent on the pH gradient across the inner membrane. To assess this strategy, we synthesized a range of TPP monoesters of the model dicarboxylate, malonate. We then tested their mitochondrial accumulation and ability to deliver malonate to isolated mitochondria and to cells, in vitro and in vivo. A TPP–malonate monoester compound, TPP11–malonate, in which the dicarboxylate group was attached to the TPP compound via a hydrophobic undecyl link, was most effective at releasing malonate within mitochondria in cells and in vivo. Therefore, we have developed a TPP–monoester platform that enables the selective release of bioactive dicarboxylates within mitochondria. |
| Databáze: | OpenAIRE |
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