Deeper insight into protease-sensitive “covalent-assembly” fluorescent probes for practical biosensing applications

Renault, Kévin; Debieu, Sylvain; Richard, Jean‐Alexandre; Romieu, Anthony

doi:10.1039/c9ob01773a

Cited by 22 publications

(26 citation statements)

References 117 publications

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“…Surprisingly, the known reactivity of pyronin dyes linked to the marked electrophilic character of their meso ‐position, has, to our knowledge, never been employed to introduce structural and functional diversity through addition of cyclic C ‐nucleophiles and subsequent spontaneous or oxidant‐mediated re‐aromatization. By analogy with an unprecedented reaction between unsymmetrical pyronin AR116 and edaravone ( i. e ., 1‐phenyl‐3‐methyl‐5‐pyrazolone, pKa 7.0 in water) occurring under simulated physiological conditions ( i. e ., phosphate buffer (PB), pH 7.5), recently highlighted by us, [15] we thought that condensation reaction between a pyronin dye and 4‐hydroxycoumarin derivatives (their C‐3 position being a latent C ‐nucleophilic center) may provide a facile and direct entry to a novel class of rosamine‐based fluorophores (Figure 1). This strategy was first implemented by mixing AR116 and 4,7‐dihydroxycoumarin in PB (100 mM, pH 7.5) with co‐solvents (PB/MeCN/DMSO, 2 : 1 : 1, v/v/v) at 60 °C for 24 h (Scheme 1, top).…”

Section: Resultsmentioning

confidence: 99%

“…[2f, 7a, 24, 27] A further argument for further practical application of these unusual rosamine dyes in biological systems was also provided by preliminary cell-imaging studies showing the cell permeability of these xanthene-based fluorophores. [11,15,28] Instruments and methods Freeze-drying operations were performed with a Christ Alpha 2-4 LD plus. Centrifugation steps were performed with a Thermo Scientific Espresso Personal Microcentrifuge instrument.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the Yang group and some of us have shown that activation of aldehyde or deprotection of primary aniline of such "caged" pyronin precursors triggered a domino cyclization-aromatization reaction leading to in situ formation of fluorescent pyronin. [15,17] A related strategy that involves Knoevenagel condensation between the benzaldehyde derivative 10 (i.e., a mixed bis-aryl ether functionalized with a formyl group and readily accessible through a copper-catalyzed Ullmann cross-coupling reaction performed under conditions reported by Anzalone et al [18] ), followed by TFA-mediated deprotection of primary aniline, has therefore been implemented (Scheme 2). 4-Hydroxy derivatives of 7hydroxycoumarin (umbelliferone), 7-N,N-dimethylaminocoumarin (DMAC), 7-N,N-diethylaminocoumarin (DEAC) and coumarin 6H were selected as latent cyclic C-nucleophiles and the optimal reaction conditions were found to be: cat.…”

Section: Synthesis Of Coumarin-pyronin Hybrid Dyes Through Formal Knomentioning

confidence: 99%

“…[e] Values determined and reported by us [15] . [f] Values determined and reported by Zhang et al [26]…”

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confidence: 99%

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Coumarin‐Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations**

Renault¹,

Chevalier

Bignon

et al. 2021

ChemPhotoChem

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A novel class of rosamine dyes bearing a 7-substituted 4-hydroxycoumarin unit as meso-heteroaryl ring is presented. The latent C-nucleophilic character of 4-hydroxycoumarin derivatives (i.e., their C-3 position as nucleophilic center) has been drawn on in the designing of two unprecedented synthetic routes towards these atypical xanthene dyes. They are based on an effective formal Knoevenagel condensation with either pyronin derivatives or a mixed bis-aryl ether bearing both an aldehyde and a masked phenylogous amine, possibly applicable to a wide range of latent cyclic C-nucleophiles. We also report experimental and theoretical photophysical investigations of these unique coumarin-pyronin hybrid structures and particularly their form low-lying quenching states, some of dark twisted intramolecular charge transfer (TICT) nature, depending on the medium (CHCl 3 and water). Furthermore, two fluorophore compounds 9 and 11 have been applied for imaging in paraformaldehyde-fixed A549 cells to gain insights into their permeation and localization. File list (2)download file view on ChemRxiv Publication-KR02-Preprint-VF.pdf (4.47 MiB) download file view on ChemRxiv Publication-KR02-Preprint-SI-VF.pdf (11.37 MiB)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Synthesis Of Coumarin-pyronin Hybrid Dyes Through Formal Knomentioning

confidence: 99%

“…[e] Values determined and reported by us [15] . [f] Values determined and reported by Zhang et al [26]…”

mentioning

confidence: 99%

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Coumarin‐Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations**

Renault¹,

Chevalier

Bignon

et al. 2021

ChemPhotoChem

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“…[64369-54-6], 7-(diethylamino)coumarin [64369-55-7] and coumarin 6H (trade name for this julolidine-based coumarin) [213481-01-7] were prepared according to literature procedures. [11,15,28] Instruments and methods Freeze-drying operations were performed with a Christ Alpha 2-4 LD plus. Centrifugation steps were performed with a Thermo Scientific Espresso Personal Microcentrifuge instrument.…”

Section: Methodsmentioning

confidence: 99%

Unprecedented Coumarin-Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations

Renault¹,

Chevalier²,

Bignon³

et al. 2021

Preprint

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A novel class of rosamine dyes bearing a 7-substituted 4-hydroxycoumarin unit as meso-heteroaryl ring is presented. The latent C-nucleophilic character of 4-hydroxycoumarin derivatives (i.e., their C-3 position as nucleophilic center) has been drawn on in the designing of two unprecedented synthetic routes towards these atypical xanthene dyes. They are based on an effective formal Knoevenagel condensation with either pyronin derivatives or a mixed bis-aryl ether bearing both an aldehyde and a masked phenylogous amine, possibly applicable to a wide range of latent cyclic C-nucleophiles. We also report experimental and theoretical photophysical investigations of these unique coumarin-pyronin hybrid structures and particularly their form low-lying quenching states, some of dark twisted intramolecular charge transfer (TICT) nature, depending on the medium (CHCl3 and water). Furthermore, two fluorophore compounds 9 and 11 have been applied for imaging in paraformaldehyde-fixed A549 cells to gain insights into their permeation and localization.

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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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Deeper insight into protease-sensitive “covalent-assembly” fluorescent probes for practical biosensing applications

Abstract: The properties and versatility of protease-responsive “covalent-assembly” fluorescent probes are optimised in an effective and rational manner, through structural diversification of their Michael acceptor moiety.

Cited by 22 publications

References 117 publications

Coumarin‐Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations**

Coumarin‐Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations**

Unprecedented Coumarin-Pyronin Hybrid Dyes: Synthesis, Fluorescence Properties and Theoretical Calculations

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

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