External‐Radiation‐Induced Local Hydroxylation Enables Remote Release of Functional Molecules in Tumors

Fu, Qunfeng; Li, Hongyu; Duan, Dongban; Wang, Changlun; Shen, Siyong; Ma, Huimin; Liu, Zhibo

doi:10.1002/anie.202005612

Cited by 38 publications

(50 citation statements)

References 37 publications

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“…We selected two major series of fluorescent cargos to be masked by mono-O-carbamylation (Figure 3b prior art in aniline disulfide redox probes, we also prepared 3-O-methyl-rhodol MR-NH 2 for kinetic comparisons. 61 Thus, all our probes feature a true off-to-on mechanistic switch of signal upon disulfide trigger cleavage, thereby maximizing their signal-to-noise ratio and simplifying analysis (details in Figure S2). We combined triggers freely with cargos to create a panel of probes for analysis.…”

Section: Resultsmentioning

confidence: 99%

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif

et al. 2021

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Specialised cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to µM concentrations), they must also be able to resist nonspecific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols, yet high selectivity for the key redox-active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will deliver redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.

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Section: Resultsmentioning

confidence: 99%

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif

et al. 2021

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“…We present the results for the synthesis of two alkylated derivatives—closed and open forms (shown in Figure 1 )—with critical reference to the methods described so far in the literature [ 26 , 27 , 28 , 29 ]. Compared to another synthesis study [ 29 ], we managed to obtain both a di- O -alkylated derivative A and an ether–ester derivative B using fluorescein. Yields of prepared fluorescein derivatives are listed in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

“…The method for synthesis of fluorescent derivative substituted as product A (3′,6′-substituted) and product B (2,6′-substituted) was reported using the same or slightly modified procedures [ 26 , 27 , 28 ]. The previous literature on the obtained derivatives have shown that it is possible to obtain 2,6′-substituted derivatives with the use of derivatives substituted in the 3′,6′ positions with practically 100% yield [ 29 ]. Given this discrepancy, we set out here to carefully investigate the fluorescein alkylation reaction.…”

Section: Introductionmentioning

confidence: 99%

Development of Efficient One-Pot Methods for the Synthesis of Luminescent Dyes and Sol–Gel Hybrid Materials

et al. 2021

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This paper presents a comparison of the simultaneous preparation of di-O-alkylated and ether–ester derivatives of fluorescein using different methods (conventional or microwave heating). Shortening of the reaction time and increased efficiency were observed when using a microwave reactor. Moreover, described here for the first time is the application of a fast, simple, and eco-friendly ball-assisted method to exclusively obtain ether–ester derivatives. We also demonstrate that fluorescein can be effectively functionalized by O-alkylation carried out under microwave or ball-milling conditions, saving time and energy and affording the desired products with good yields and minimal byproduct formation. All the synthesized products as well as pH-dependent (prototropic) forms trapped in the SiO2 matrix were examined using UV–Vis and fluorescence spectroscopy.

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“…Recently, Liu et al reported the radiation-triggered unmasking of functional molecules, which provided a proof-of-concept study of remote activation in vivo . 132 Beyond this proof-of-concept study, new methods for remote decaging/release that are suitable not only for living animals but also for humans may appear in the near future.…”

Section: Discussionmentioning

confidence: 99%

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

et al. 2021

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Bioorthogonal cleavage chemistry has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomolecules in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomolecules, the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small molecules as well as biomacromolecules in living systems, allowing multidimensional controls over biological processes in vitro and in vivo . In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chemical structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chemical labeling.

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External‐Radiation‐Induced Local Hydroxylation Enables Remote Release of Functional Molecules in Tumors

Cited by 38 publications

References 37 publications

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif

Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif

Development of Efficient One-Pot Methods for the Synthesis of Luminescent Dyes and Sol–Gel Hybrid Materials

Unleashing the Power of Bond Cleavage Chemistry in Living Systems

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