Triphenylphosphonium (TPP)‐Based Antioxidants: A New Perspective on Antioxidant Design

Wang, Jiayao; Li, Jiaqi Q.; Xiao, Yumei; Fu, Bin; Qin, Zhaohai

doi:10.1002/cmdc.201900695

Cited by 51 publications

(32 citation statements)

References 82 publications

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“…As triphenylphosphine is an essential building block of mitochondria-targeted antioxidants and neoplastic agents [ 13 , 14 ], e.g., lipophilic triphenylphosphonium cations, we aimed to synthesize the paramagnetic analog of triphenylphosphine. We intended to determine whether or not we can synthesize different types of nitroxide-containing mitochondrially targeted molecules compared to MITO-CP ( Figure 1 ) [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine

et al. 2021

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The reaction of a diene nitroxide precursor with dichlorophenylphosphine in a McCormac procedure afforded 1,1,3,3-tetramethyl-5-phenyl-1,2,3,4,5,6-hexahydrophospholo[3,4-c]pyrrole-5-oxide-2-oxyl. Lithiation of the protected 3-iodo-pyrroline nitroxide followed by treatment with chlorodiphenylphosphine after deprotection afforded (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine oxide, and after reduction, (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine was realized, which was also supported by X-ray single crystal diffraction measurements. This pyrroline diphenylphosphine derivative was converted to hexadecylphosphonium salt, which is an analogue of antineoplastic agent, MITO-CP.

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Section: Resultsmentioning

confidence: 99%

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine

et al. 2021

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“…Fundamentally, this compound includes an ubiquinone moiety covalently adhered to a terminal aliphatic 10-carbon chain with a triphenylphosphonium complex (TPP + ); that is the lipophilic cation that stores several hundred-fold in the mitochondria [15,16]. One of the most classical functions of this type of phosphonium salts is to increase the mitochondrial tropism of antioxidant molecules [17]; as over 95% of the cellular ROS produced by cells is the consequence of mitochondrial activity [18].…”

Section: Introductionmentioning

confidence: 99%

Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels

Méndez

Arauna

Fuentes

et al. 2020

IJMS

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Platelet activation plays a key role in cardiovascular diseases. The generation of mitochondrial reactive oxygen species (ROS) has been described as a critical step required for platelet activation. For this reason, it is necessary to find new molecules with antiplatelet activity and identify their mechanisms of action. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces mitochondrial overproduction of ROS. In this work, the antiplatelet effect of MitoQ through platelet adhesion and spreading, secretion, and aggregation was evaluated. Thus MitoQ, in a non-toxic effect, decreased platelet adhesion and spreading on collagen surface, and expression of P-selectin and CD63, and inhibited platelet aggregation induced by collagen, convulxin, thrombin receptor activator peptide-6 (TRAP-6), and phorbol 12-myristate 13-acetate (PMA). As an antiplatelet mechanism, we showed that MitoQ produced mitochondrial depolarization and decreased ATP secretion. Additionally, in platelets stimulated with antimycin A and collagen MitoQ significantly decreased ROS production. Our findings showed, for the first time, an antiplatelet effect of MitoQ that is probably associated with its mitochondrial antioxidant effect.

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“…To examine the effect of TIPTP in a colitis model, we tested TIPTP with additional chemical moiety in BMDMs. To increase the specificity of TIPTP for targeting mitochondria, we added a molecule called TPP, which is primarily used for mitochondrial targeting [ 33 ]. We designated this compound, Mito-TIPTP, which exhibits a higher capacity to target mitochondria compared with TIPTP (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

Kim

Jang

et al. 2021

Antioxidants

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The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

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Triphenylphosphonium (TPP)‐Based Antioxidants: A New Perspective on Antioxidant Design

Cited by 51 publications

References 82 publications

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine

Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

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