Alkyl vs. aryl modifications: a comparative study on modular modifications of triphenylphosphonium mitochondrial vectors

Abstract

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...

Beyond the TPP+“gold standard”: a new generation mitochondrial delivery vector based on extended PN frameworks

“… 48 It has been previously established that an increase in log P is generally well correlated with an increase in mitochondrial accumulation. 15,18,20 Relative to compound 1 (log P = −1.36), – the current “gold-standard” – compound 2 had a marginally higher log P of −1.28, but displayed a much higher IC 50 , which goes against the expected trends. We attributed this discrepancy to the increased ion-pairing tendency of this compound ( vide infra ).…”

“…We have then increased the compound dataset to include previously tested cations (including dications) from our previous reports (compounds 8 -23 in Figure S4 and Table S4). 15,18,20 This enlarged dataset made up a total of 21 cations (16 additional compounds) with a series of experimental correlations shown in Figure S5.…”

“…To investigate the mitochondrial targeting ability of the PPN + moiety, it was conjugated to a fluorescein derivative previously reported in the literature. 15,52 However, to control regioselectivity and eliminate the protonophoric site, a methyl ester of fluorescein was employed to avoid mixtures of products. An analogous TPP + variant was also synthesised as a control.…”

“…14 Due to the success in applying triphenylphosphonium (TPP + ) systems for mitochondrial delivery, there is an increasing interest in modifying the TPP + systems for enhanced delivery. [15][16][17][18][19][20][21][22][23] Although they are often referred to as DLCs, 6,24,25 in the context of TPP + systems, the necessity of charge delocalisation for mitochondrial accumulation is ambiguous. In contrast with DLCs such as rhodamines and cyanines, TPP + moieties do not typically contain polyaromatic or extended conjugated Please do not adjust margins Please do not adjust margins moieties.…”

Polarity-Ultrasensitive and Lipophilicity-Enhanced Structurally Modified Hemicyanine for Two-Color Staining to Reveal Cell Apoptosis during Chemotherapy

“…The development of imaging tools to monitor the microenvironment in mitochondrial is fruitful as there are plenty of fluorescence sensors employed for tracing mitochondrial action in the pathological and physiological courses . Also, some polarity-sensitive fluorescence sensors revealed detailed cellular actions by tracing cell autophagy. − Szeto-Schiller peptide and mitochondria penetrating peptide are employed as delivery agents for mitochondria targeting. − The traditional molecular mitochondria markers comprise cyanine, rhodamine, and triphenylphosphonium cation, which are extensively equipped with functional groups for mitochondrial import and chemical sensing. − The exploitation of versatile microenvironment sensors would benefit from the use of integrated delivery vector and sensing moiety for the precise measurement of local polarity, as the sensing signal transmission is facile throughout the adjacent molecular structure. − The commercially available apoptosis kits are Annexin-V-FITC/propidium iodide and Annexin-V-PE/7-AAD, which are widely utilized in cellular apoptosis monitoring for chemical biology. However, this strategy needs intrinsically labile agents, generally complicated washing procedures with specialized storage conditions, which is more susceptible to false-positive results .…”