Synthesis, stability, and metal chelator interactions of triphenylphosphonium conjugates
Creators: name: Gruenwald, Hannah
Publisher: name: University of Iowa
Year: 2022
Subjects: subject: DMSO
subject: DTPA
subject: Metal Chelators
subject: Mitochondria
subject: Triphenylphosphonium
subject: public abstract
subject: Organic Chemistry
subject: FOS: Chemical sciences

description: Mitochondria are organelles in eukaryotic cells that play an essential role in various processes including those regulating cellular life and death. One of the main functions of the mitochondria is to generate ATP through oxidative phosphorylation (OXPHOS), which is the process of oxidizing nutrients to release chemical energy. Dysfunction of the mitochondria can lead to several disease states and very often leads to cell death. Because of the role of mitochondria in several physiological processes necessary for survival and the various disease states that exist because of dysfunctional mitochondria, mitochondria are an important target for probes and medications for therapeutic intervention.
description: Triphenylphosphonium (TPP+) is a diffused lipophilic cation known for its tendency to accumulate in the mitochondria. Because of this, it is commonly used in drug conjugates and probes to direct cargo to the mitochondria. TPP+ effectively targets mitochondria because of its lipophilic and diffused cationic character. These qualities allow TPP+ to readily cross lipid bilayer membranes and accumulate across the negative inner mitochondrial membrane against their concentration gradient, respectively.
description: While TPP+ is effective in mitochondrial accumulation, it has been shown to cause a dose- mediated uncoupling of OXPHOS, which depolarizes the mitochondrial membrane and leads to cell death. Previous research has identified phenyl-substituted conjugates with modulated uncoupling potential as a function of the electron-density on the central phosphorus atom of TPP+. Electron-donating substituents such as methoxy increase the electron density on the central phosphorus atom and cause a relative increase in uncoupling potential as compared to unsubstituted TPP+. Electron-withdrawing substituents such as trifloromethyl (CF3) decrease the electron density of the central phosphorus cation, and effectively decrease dose-mediated uncoupling of OXPHOS.
description: The first goal of this work was to develop novel TPP+ conjugates with electron-withdrawing phenyl substitutions for further analysis for mitochondrial uncoupling potential and cytotoxicity. This was attempted by three different approaches, first to change the identity of the phenyl substituents on TPP+, second to change the number of substituted phenyls on phosphonium conjugates, and third to change the number of substitutions on triphenylphosphonium. Though modulating the identity and quantity of electron-withdrawing groups, it was hypothesized that uncoupling potential could be modulated in a step-wise fashion.
description: The second goal of this work was to analyze the stability of the previously reported CF3-para- substutited conjugate with decyl linker (CF3-TPP+-DC) after potential stability concerns with this conjugate had been identified. This section aimed to monitor the stability of CF3-TPP+-DC in a variety of experimentally relevant buffers and solvents, as well as biologically relevant conditions that mimic environments found in the mitochondria.
description: Results of the stability experiments suggested a potential interaction between CF3-TPP+-DC and the metal chelator, DTPA, which led to the final goal of this dissertation, to probe potential interactions between metal chelators of divalent cations and TPP+ conjugates. This section aimed to elucidate interactions between EDTA, DTPA, and Chelex100 with TPP+-based drugs and probes.
description: Results of these studies identify specific conditions that cause degradation of CF3-TPP+-DC, and several conditions of stability for previously reported TPP+ conjugates and commercially available probes. These studies identify and provide the first report of interactions between metal chelators and TPP+ conjugates, including commercially available probes.