Enabling Mitochondrial Uptake of Lipophilic Dications Using Methylated Triphenylphosphonium Moieties

Ong, How Chee; Zhang, Hu; Coimbra, João T. S.; Ramos, María J.; Kon, Oi Lian; Xing, Bengang; Yeow, Edwin K. L.; Fernandes, Pedro A.; Garcı́a, Felipe

doi:10.1021/acs.inorgchem.8b03380

Cited by 21 publications

(39 citation statements)

References 47 publications

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“…Our present work is part of an ongoing collaborative project on the development of novel, mitochondriotropic chemiluminescent probes for ROS detection. In this regard, we opt for the synthesis of tailor-designed luminol and isoluminol (the 6-amino isomer of luminol) derivatives, covalently linked with phosphonium cations as mitochondriotropic moieties [29,30,31]. Herein, we report on the synthesis and chemiluminescent properties of amino-acylated luminol and isoluminol derivatives bearing variable phosphonium cations (triphenyl, tris(4-tolyl) or tricyclohexyl) and chain lengths (hexyl, undecyl).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Chemiluminescent Properties of Amino-Acylated luminol Derivatives Bearing Phosphonium Cations

et al. 2019

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The monitoring of reactive oxygen species in living cells provides valuable information on cell function and performance. Lately, the development of chemiluminescence-based reactive oxygen species monitoring has gained increased attention due to the advantages posed by chemiluminescence, including its rapid measurement and high sensitivity. In this respect, specific organelle-targeting trackers with strong chemiluminescence performance are of high importance. We herein report the synthesis and chemiluminescence properties of eight novel phosphonium-functionalized amino-acylated luminol and isoluminol derivatives, designed as mitochondriotropic chemiluminescence reactive oxygen species trackers. Three different phosphonium cationic moieties were employed (phenyl, p-tolyl, and cyclohexyl), as well as two alkanoyl chains (hexanoyl and undecanoyl) as bridges/linkers. Synthesis is accomplished via the acylation of the corresponding phthalimides, as phthalhydrazide precursors, followed by hydrazinolysis. This method was chosen because the direct acylation of (iso)luminol was discouraging. The new derivatives’ chemiluminescence was evaluated and compared with that of the parent molecules. A relatively poor chemiluminescence performance was observed for all derivatives, with the isoluminol-based ones being the poorest. This result is mainly attributed to the low yield of the fluorescence species formation during the chemiluminescence oxidation reaction.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Chemiluminescent Properties of Amino-Acylated luminol Derivatives Bearing Phosphonium Cations

et al. 2019

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“…An effective strategy for enhancing mitochondrial uptake has been focused around tuning the molecule's lipophilicity, which has been demonstrated to be highly relevant for TPP + -conjugated systems. [20][21][22][23][24] The typical strategy for enhancing lipophilicity for TPP + -conjugated compounds is by selecting a molecular fragment (module) with a higher lipophilicity as the linker -usually a longer alkyl chain 6,23,24 -between the TPP + moiety and the cargo, which increases the rate of membrane permeation and hence the mitochondrial accumulation. 25 However, chain length modulation has its limitations.…”

Section: Introductionmentioning

confidence: 99%

Alkyl vs Aryl Modifications: A Comparative Study on Modular Modifications of Triphenylphosphonium Mitochondrial Vectors

Ong¹,

Coimbra²,

Ramos³

et al. 2021

Preprint

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Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provides further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications<br>

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“…This is due to the large activation energy needed to remove the aqueous solvation shell for movement of the ion into the hydrophobic membrane core (Born energy). 12 , 20 Image forces and dipole interactions with the phospholipid esters also hinder TPP uptake; however, these contribute far less than the Born energy. 12 , 20 By introducing hydrophobic phenyl groups, the charge is spread over a larger area, and steric hindrance distances the water molecules from the charge; thus, the solvent-accessible charge is lower, and the free energy required to remove water molecules for partitioning into the membrane is reduced.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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, TPP 11 –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.

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Enabling Mitochondrial Uptake of Lipophilic Dications Using Methylated Triphenylphosphonium Moieties

Cited by 21 publications

References 47 publications

Synthesis and Chemiluminescent Properties of Amino-Acylated luminol Derivatives Bearing Phosphonium Cations

Synthesis and Chemiluminescent Properties of Amino-Acylated luminol Derivatives Bearing Phosphonium Cations

Alkyl vs Aryl Modifications: A Comparative Study on Modular Modifications of Triphenylphosphonium Mitochondrial Vectors

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

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