An Innovative Hydrogen Peroxide‐Sensing Scaffold and Insight Towards its Potential as an ROS‐Activated Persulfide Donor

Hankins, Rynne A.; Suarez, S. Israel; Kalk, Madison A.; Green, Nolan M.; Harty, Megan N.; Lukesh, John C.

doi:10.1002/anie.202010530

Cited by 32 publications

(30 citation statements)

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“…The reported ROS‐activated prodrugs are mainly released through hydrogen peroxide‐mediated oxidative deboronization [9d,g,l] or superoxide anion radical‐mediated diphenylphosphine cleavage [9j] . In this work, we attempt to discover novel persulfide prodrugs triggered by peroxynitrite.…”

Section: Resultsmentioning

confidence: 99%

“…While designing and preparing prodrugs, we also endeavored to verify the feasibility of persulfide release through self‐reported fluorescent probes with 2‐oxo‐2‐phenylacetamide trigger, inspired by the previous works of Matson [9d] and Lukesh [9l] . A linear synthetic route (Scheme 2A) was adopted, resulting from the failure of coupling between thiol 5 d and WSP‐2 [19] .…”

Section: Resultsmentioning

confidence: 99%

“…Most recently, an array of persulfide prodrugs (also known as persulfide donors) have emerged, igniting a better understanding of the possible role of persulfides as protectants against oxidative stress [9] . From a structural perspective, the available prodrugs can be broadly classified into two groups, one marked by acyl persulfide moieties that can undergo intramolecular acyl migration [9a,c,f,k,l] and the other by asymmetric disulfides containing stimulant cleavable groups (Figure 1). [9b,d,e,g–j,m] And from a perspective of stimulus type, four activation modes exist, namely enzyme‐activated, [9b,c,i,m,n] pH‐dependent, [9a,e,f,k] light‐activated, [9h] and reactive oxygen species (ROS)‐activated prodrugs [9d,g,j,l] .…”

Section: Introductionmentioning

confidence: 99%

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Peroxynitrite‐Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning

Wang

et al. 2022

Chemistry A European J

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The newly emerging persulfide prodrugs provide additional options for the profound study of persulfide, a fascinating molecule expected to intervene in biological functions and even diseases. Peroxynitrite is often the culprit in pathological processes characterized by oxidative stress, while the persulfide prodrug responsive to it is still pending. To enrich the family of redox-activated prodrugs, we designed prodrugs with a 2-oxo-2-phenylacetamide trigger, which achieved the release of persulfide via 1, 6-N, S-relay.The degradation of prodrugs and the formation of persulfides were confirmed to be peroxynitrite-responsible by the qualitative and quantitative studies based on LC-MS/MS methods and a spectrophotometry-based tag-switch strategy. Furthermore, these prodrugs showed potent peroxynitrite scavenging activity, cellular therapeutic potential against paracetamol poisoning in HepG2 and oxidative stress in H9c2, as well as desirable in vitro metabolic properties.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peroxynitrite‐Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning

Wang

et al. 2022

Chemistry A European J

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“…Another H 2 O 2 -responsive persulfide donor was recently reported by Lukesh et al, drawing inspiration from Wang to synthesize TML-containing analogues with H 2 O 2 -sensitive Bpin triggers . The authors designed and synthesized a self-reporting, ROS-responsive persulfide donor, equipped with both a disulfide functionality and 7-hydroxycoumarin.…”

Section: Synthetic Persulfide Donorsmentioning

confidence: 99%

A Review of Chemical Tools for Studying Small Molecule Persulfides: Detection and Delivery

Dillon

Matson

2021

ACS Chem. Biol.

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Hydrogen sulfide (H2S) has gained significant attention as a potent bioregulator in the redox metabolome, but it is just one of many reactive sulfur species (RSS). Recently, small molecule persulfides (structure RSSH) have emerged as RSS of particular interest due to their enhanced antioxidant abilities compared to H2S and their ability to directly convert protein thiols into protein persulfides, suggesting that persulfides may have distinct physiological functions from H2S. However, persulfides exhibit instability and cross-reactivity that hampers the elucidation of their precise biological roles. As such, chemists have designed chemical tools and techniques to facilitate the study of persulfides under various conditions. These molecules and methods include persulfide trapping reagents and sensors, as well as compounds that degrade in response to various triggers to release persulfides, termed persulfide donors. There now exist a variety of persulfide donor classes, some of which possess tissue-targeting capabilities designed to mimic localized endogenous production of RSS. This Review briefly covers the physicochemical properties of persulfides, the endogenous production of small molecule persulfides, and their reactions with protein thiols and other reactive species. These introductory sections are followed by a discussion of chemical tools used in persulfide chemical biology, with critical analysis of recent advancements in the field and commentary on potential directions for future research.

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“…2020 年, Lukesh 等[24] 再次选择苯硼酸酯作为 ROS 特异性触发基团, 并借助"trimethyl lock"前药策略, 设计了一类新型 RSSH 供体 9 (RAH393), 其释放过程与供体 3 类似(图 7). 为了验证这一设计的合理性, 研究者将供体离去基团替换为 7-HCm 与试卤灵(Resorufin), 合成了荧光探针 10 (RAH225)及 11 (RAH2115), 两类探针的激活均呈现较好的 H 2 O 2 特异性.…”

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Research Progress of Small-Molecular Hydropersulfide Donors

Xu¹,

Wang²,

Zhen³

et al. 2021

Chinese Journal of Organic Chemistry

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The unique chemical structure endowed small-molecular hydropersulfides (RSSH) with unclear but fascinating biological activities, which have been attracted much attention. The donors that could release RSSH smoothly in situ under physiological or pathological conditions will become powerful chemical tools for exploring the physiological functions, mechanism of action, and potential therapeutic benefit of RSSH. Over the past five years, a substantial breakthrough had been achieved in the design and development of RSSH donors, which is summarized in this perspective. According to the activation patterns, the existing donors are divided into five categories, namely esterase-activated donor, ROS (reactive oxygen species)-activated donor, pH-dependent donor, light-activated donor, and nitroreductase-activated donor. All kinds of donors played ideal roles in improving the oxidative stress at the cellular level, part of which also show a positive therapeutic effect in the context of myocardial ischemia-reperfusion injury. Besides, the related release mechanisms and the proof of concept of the donors are briefly introduced. In the next five years, waves of novel donors are emerging. On one hand, diverse donors, with stable and controllable release rate, clear release process, and identified release components, will be designed. On the other hand, the indispensable toolbox of donors will be fully assembled for more in-depth and comprehensive biological activity researches.

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An Innovative Hydrogen Peroxide‐Sensing Scaffold and Insight Towards its Potential as an ROS‐Activated Persulfide Donor

Cited by 32 publications

References 64 publications

Peroxynitrite‐Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning

Peroxynitrite‐Promoted Persulfide Prodrugs with Protective Potential against Paracetamol Poisoning

A Review of Chemical Tools for Studying Small Molecule Persulfides: Detection and Delivery

Research Progress of Small-Molecular Hydropersulfide Donors

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