A small molecule probe reveals declined mitochondrial thioredoxin reductase activity in a Parkinson's disease model

Liu, Yaping; Ma, Haiying; Zhang, Liangwei; Cui, Yue; Liu, Xiaoting; Fang, Jianguo

doi:10.1039/c5cc09998f

Cited by 62 publications

(36 citation statements)

References 38 publications

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“…Such prodrugs are expected to display high efficacy to those TrxR‐overexpressing cancer cells with less side effects on noncancerous cells. In our previous studies, we developed several fluorescent probes for mammalian TrxRs (TrxR fluorogenic substrates, TRFS series). These probes contain a five‐membered cyclic disulfide (1, 2‐dithiolane) scaffold, which can be efficiently reduced by TrxRs in the presence of NADPH but is resistant to other related enzymes and biological thiols.…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

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131

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

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131

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“…However, only a few fluorescent probes for TrxR have been reported so far. [37][38][39] The first fluorescent probe for TrxR, 8 (Scheme 3), was developed by Zhang et al 37 in 2014. A naphthalimide moiety serves as the fluorophore in this substance because of its outstanding light-emission characteristics, and a five-membered, cyclic disulfide scaffold, which can be selectively cleaved by TrxR in the presence of NADPH, serves as the reaction center.…”

Section: Fluorescent Probes For Trxrsmentioning

confidence: 99%

“…This probe was successfully applied to imaging TrxR activity in living cells and has the potential to be used for screening TrxR inhibitors in live cells, an important step for developing TrxR-targeted anticancer drugs. After this effort, Liu et al 38 designed and synthesized another mitochondrial targeting TrxR probe 9, which incorporates a triphenylphosphonium moiety into the parent probe 8 (Scheme 3). Probe 9, which is selective for TrxR2 (mainly localized within mitochondria), has been applied to assays of the enzyme in a model of Parkinson disease(PD) .…”

Section: Fluorescent Probes For Trxrsmentioning

confidence: 99%

Fluorescent Probes Containing Selenium as a Guest or Host

Chen

Kwon

et al. 2016

Chem

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Selenium is an important trace element in living systems. Proteins incorporating selenium have a wide range of biological effects, ranging from anti-oxidant and antiinflammatory effects to the production of active thyroid hormones. In the past decades, selenium has drawn enormous attention because of its important role in biology, which can be ascribed partly if not solely to its redox and hard and soft donor properties. With the use of chemical mimicry, a large number of seleniumrelated fluorescent probes have been developed for monitoring physiological and pathological processes. This review, which summarizes recent progress made in this area, comprises two major sections. In the first section, fluorescent probes for selenium-containing species, such as selenocysteine (Sec), hydrogen selenide, thioredoxin reductases (TrxRs), and selenite, are described. This is followed by a discussion of fluorescent probes that contain selenium and detect reactive oxygen, nitrogen, and sulfur species, as well as cations and anions.

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“…The fluorogenic TRFS probes 14,16,32,33 and prodrugs 15 have been commercialised and extensively reviewed [34][35][36][37][38] (Fig 1e; overview in Fig S1b). These probes have since been used to study the role of TrxR in Parkinson's disease 39 and stroke 33 , and have been employed for mechanistic validation of putative TrxR inhibitors during screening approaches. 16 Which is the real situation?…”

Section: Introductionmentioning

confidence: 99%

Cyclic 5-Membered Disulfides Are Not Selective Substrates of Thioredoxin Reductase, but Are Opened Nonspecifically by Thiols

Felber¹,

Poczka²,

Busker³

et al. 2020

Preprint

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<div> <div> <div> <p>The cyclic five-membered disulfide 1,2-dithiolane has been used as the key element in numerous chemical biology probes. Contradictory views of this disulfide motif populate the literature: some reports describe it as being nonspecifically reduced, others as a highly specific substrate for thioredoxin reductase (TrxR). We show that 1,2-dithiolanes are nonspecifically reduced by a broad range of thiol reductants and redox-active proteins, and that their cellular performance is barely affected by TrxR inhibition or knockout. We conclude that inhibitor screenings and probe designs treating 1,2-dithiolanes as TrxR-selective substrates should be treated with caution and previous interpretations may need careful re-evaluation. Considering ring-opening polymerisation, and stringently interpreting assays involving the thiophilic gold-based inhibitor auranofin, are critical to assess 1,2-dithiolane’s true behaviour. We present an approach to control against assay misinterpretation with reducible probes, to ensure that future TrxR-targeted designs are robustly evaluated for selectivity, and to better orient redox probe research in the future. </p> </div> </div> </div>

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A small molecule probe reveals declined mitochondrial thioredoxin reductase activity in a Parkinson's disease model

Cited by 62 publications

References 38 publications

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Fluorescent Probes Containing Selenium as a Guest or Host

Cyclic 5-Membered Disulfides Are Not Selective Substrates of Thioredoxin Reductase, but Are Opened Nonspecifically by Thiols

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