Fluorogenic Enzyme-Triggered Domino Reactions Producing Quinoxalin-2(1<i>H</i>)-one-based Heterocycles

Dejouy, Garance; Renault, Kévin; Bonnin, Quentin; Chevalier, Arnaud; Michaudet, Cédric; Picquet, Michel; Valverde, Ibai E.; Romieu, Anthony

doi:10.1021/acs.orglett.0c02287

Cited by 8 publications

(4 citation statements)

References 62 publications

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“…As previously stated in our recent contributions devoted to analytical validations of "covalent-assembly" fluorescent probes, it is of prime importance to combine conventional fluorescence-based assays with complementary RP-HPLCfluorescence and RP-HPLC-MS analyses. [23] Indeed, this is the only way for assessing both efficacy and selectivity of the studied fluorogenic cascade reaction (conversion rate and possible formation of side-products?) and thus deciphering precisely the activation mechanism of such reaction-based fluorescent probes.…”

Section: In Vitro Validations Of Pga-responsive "Covalent-assembly" F...mentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Renault

Capello

Yao

et al. 2023

Chemistry An Asian Journal

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Latent cyclic carbon‐centered nucleophiles (latent C‐nucleophiles) are recently proving their value in the field of reaction‐based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C‐nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug‐releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the “covalent‐assembly” principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine‐2,4‐dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme‐responsive caged precursors of fluorescent pyronin dyes and 7‐(diethylamino)coumarin‐3‐carboxylic acid, led to identify a versatile candidate suitable for this late‐stage structural optimization approach. This Meldrum's acid derivative enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate‐based theranostics.

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Section: In Vitro Validations Of Pga-responsive "Covalent-assembly" F...mentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Renault

Capello

Yao

et al. 2023

Chemistry An Asian Journal

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“…Subsequent O-alkylation with para-(phenylacetamido)benzyl bromide 15 [20] was performed under conditions previously optimized by us, to install the PGA recognition moiety onto phenolic hydroxyl groups. [21] Further treatment of the resulting phenylacetamide derivative 16 with p-TSA in aqueous THF at 40 °C [18] , gave the benzaldehyde 17. Final Knoevenagel condensation with Meldrum's acid derivative 3 [10c] using conditions described above for the preparation of Michael adduct 7, led to the desired fluorogenic PGA substrate 18.…”

Section: Screening Of Functionalized Latent Cyclic C-nucleophiles And...mentioning

confidence: 99%

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

Renault

Capello

Yao

et al. 2023

Preprint

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Latent cyclic carbon-centered nucleophiles (latent C-nucleophiles) are recently proving their value in the field of reaction-based fluorescent probes, far beyond their primary utility in organic synthesis. They are typically used to introduce a Michael acceptor moiety acting as a recognition/reaction site for analyte to be detected or as a kinetic promoter of fluorogenic cascade reactions triggered by a reactive species. C-nucleophiles bearing a further reactive handle offer an additional opportunity for tuning the physicochemical/targeting properties or providing drug-releasing capabilities to these probes, through the covalent attachment of ad hoc chemical moiety. In order to implement such strategy to fluorogenic/chromogenic enzyme substrates based on the "covalent-assembly" principle, we have explored the potential of some functionalized derivatives of barbituric acid, piperidine-2,4-dione and Meldrum's acid. Our investigations based on the rational design and analytical validations of enzyme-responsive caged precursors of fluorescent pyronin dyes and 7-(diethylamino)coumarin-3-carboxylic acid, led to identify a versatile candidate suitable for this late-stage structural optimization approach with a minor impact on stability and activation kinetics of probe. This Meldrum's acid derivative, synthesized from levulinic acid, enables to either enhance water solubility or achieve the reversible conjugation of a targeting ligand, while promoting in situ formation of fluorophore upon enzymatic activation. This study opens the way to novel multifunctional fluorescence imaging probes and optically modulated small conjugate-based theranostics drawing on the promising "covalent-assembly" strategy.

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“…In 2020, Romieu and Renault reported enzyme‐activated probes based on the in situ and quantitative formation of fluorescent quinoxalin‐2(1 H )‐ones [66] . This fluorescence uncaging approach, named “covalent assembly”, aims at dramatically improving signal‐to‐noise ratio responses by generating quantitatively a fluorescent backbone from a non‐fluorescent precursor.…”

Section: Applicationsmentioning

confidence: 99%

“…In 2020, Romieu and Renault reported enzyme-activated probes based on the in situ and quantitative formation of fluorescent quinoxalin-2(1H)-ones. [66] This fluorescence uncaging approach, named "covalent assembly", aims at dramatically improving signal-to-noise ratio responses by generating quantitatively a fluorescent backbone from a non-fluorescent precur- sor. This strategy involved an effective biocompatible cyclization/aromatization domino process triggered by penicillin G acylase (PGA) from caged o-phenylenediamine substrates 163 (Scheme 23).…”

Section: Fluorescence-based Molecular Probes For Detecting Enzymatic ...mentioning

confidence: 99%

Quinoxalin‐2(1H)‐ones: Chemical Synthesis, Fluorescence Properties and Applications

2022

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Photophysical properties of quinoxalin-2(1H)-ones have long been neglected, in particular compared with those of coumarins, their oxygenated counterparts, despite their complementarity in terms of absorbance and fluorescence windows. This review provides first an overview of the synthesis of quinoxalin-2(1H)-ones, focusing on the most recent contributions. Fluorescence properties of quinoxalin-2(1H)-ones and of their π-extended derivatives are tackled through the description of a series of examples and applications, including chemosensing and biosensing. www.eurjoc.org

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Fluorogenic Enzyme-Triggered Domino Reactions Producing Quinoxalin-2(1H)-one-based Heterocycles

Abstract: Experimental procedures, spectroscopic and analytical data, IR, NMR, MS and UV-vis/fluorescence spectra, elution profiles for all RP-HPLC-fluorescence/-MS analyses (PDF). The Supporting Information is available free of charge at xxx.

Cited by 8 publications

References 62 publications

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme‐Responsive “Covalent‐Assembly” Fluorescent Probes with Tailor‐Made Properties**

Arylidene Meldrum's Acid: A Versatile Structural Motif for the Design of Enzyme-Responsive "Covalent-Assembly" Fluorescent Probes with Tailor-Made Properties

Quinoxalin‐2(1H)‐ones: Chemical Synthesis, Fluorescence Properties and Applications

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