Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Abstract

Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

“…However,d ue to the unselective nature of most molecular ion sensors,such an assay would not be compatible with complex mixtures of ions.Apotential solution to this challenge could be to utilize an analytical technique that readily detects multiple metals by their unique emission energies.W ep ostulate that an optimal in vitro measurement system could be realized by incubating LUVs,o ra nother setup having two membrane-separated compartments,w ith ac ombination of alkali and transition metal ions in the presence of an ionophore to create asituation of competition between the ions.F or analysis,t he individual compartments must be directly addressable for sampling or the ion exchange reaction needs to be rapidly terminated before the samples can be processed for identification and quantification of the compartment-entrapped ions,f or example,b yi nductively coupled plasma optical emission spectrometry (ICP-OES). [92] Fordetailed analyses of ionophore activities,however, subcellular specificity is required and although small molecules are easily targeted to active mitochondria by incorporation of lipophilic cations, [93] other organelles are more difficult to target by small molecules.I ft he ionophore perturbs the membrane potential of the mitochondria, this method for mitochondrial targeting might not be suitable. [88][89][90] Small-molecule ion sensors,although subject to constant improvements,are notoriously unselective between ions and can exert nonrelated secondary effects; [91] this calls for caution if they are employed for analysis of ion transport in cellular systems.Despite these challenges,highly selective ion sensors for, for example,C u + and Cu 2+ have been developed and rigorously characterized in cells and in vivo.…”

Chemische Synthesen und chemische Biologie von Carboxylpolyether‐Ionophoren: Aktuelle Entwicklungen

“…Allerdings sind wegen der unselektiven Natur der meisten molekularen Ionensensoren solche Assays nicht kompatibel mit komplexen Mi- metallionen in Gegenwart des Ionophors,u me ine Konkurrenzsituation zwischen den Ionen zu herzustellen. [92] Fürd etaillierte Analysen von Ionophor-Aktivitäten ist hingegen eine subzelluläre Spezifitäte rforderlich, und obwohl kleine Moleküle durch die Einführung lipohiler Kationen auf einfahce Weise aktive Mitochondrien targetieren kçnnen, [93] sind andere Organellen schwierig anzusteuern. B. mçglich durch optische Emissionsspektrometrie mit induktiv gekoppeltem Plasma (ICP-OES).…”

Two‐photon fluorescence lifetime imaging of intrinsic NADH in three‐dimensional tumor models

“…The novel cyano-4-hydroxycinnamic acid-based compound MD1 that inhibits MCT1 and MCT4 (8) and a triphenylphosphonium bromide derivative (TPPBr) that targets mitochondria (41,42) were used to examine the metabolic response of 4T1 in 2D and 3D cultures. The chemical structures of MD1 and TPPBr are shown in Figure 2.…”

“…These compounds, currently being studied for their suitability as anticancer agents, include a cyano-4-hydroxycinnamic acid-based monocarboxylate transporter (MCT) inhibitor called MD1 (41), and an alkoxycarbonylallyl-based alkylator modified with a triphenylphosphonium group to target mitochondria and disrupt OXPHOS (42), called TPPBr. Toward this purpose, we report here the impact of a three-dimensional (3D) collagenous ECM on the metabolic responses of metastatic breast cancer cells to two novel inhibitors of MCTs and OXPHOS.…”