Design, synthesis and evaluation of enzyme-responsive fluorogenic probes based on pyridine-flanked diketopyrrolopyrrole dyes

Jenni, Sébastien; Ponsot, Flavien; Baroux, Pierre; Collard, Lucile; Ikeno, Takayuki; Hanaoka, Kenjiro; Quesneau, Valentin; Renault, Kévin; Romieu, Anthony

doi:10.1016/j.saa.2020.119179

Cited by 6 publications

(11 citation statements)

References 66 publications

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“…Subsequent O-alkylation with para-(phenylacetamido)benzyl bromide 15 [21] was performed under conditions previously optimized by us, to install the PGA recognition moiety onto phenolic hydroxyl groups. [22] Further treatment of the resulting phenylacetamide derivative 16 with p-TSA in aqueous THF at 40 °C, [19] gave the benzaldehyde 17.…”

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

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: 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

Chemistry An Asian Journal

Self Cite

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show abstract

“…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.…”

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

confidence: 99%

“…were prepared according to literature procedures. [10a],[10c], [14], [37], [20], [38], [28], [35], [39]…”

Section: Generalmentioning

confidence: 99%

“…The recovered impure product was subjected to a second purification by semi-preparative RP-HPLC (system C, tR = 20.0-21.0 min). After freeze-drying, a pure sample of PGA-responsive probe 7 was recovered as an orange amorphous powder (20 6.81 (ddd, J = 7.7, J = 2.4, J = 1.3 Hz, 1H), 6.67 (dd, J = 9.6, J = 2.5 Hz, 1H), 6.08 (d, J = 2.5 Hz, 1H), 3.62 (s, 2H), 3.40 (q, J = 7.1 Hz, 4H), 2.40 (t, J = 7.6 Hz, 2H), 2.21 (hept, J = 7.1 Hz, 2H), 1.66 (s, 3H), 1.05 (t, J = 7.0 Hz, 6H); 13…”

Section: Meldrum's Acid-based Pga-sensitive Probementioning

confidence: 99%

“…Thereafter, the mixture was cooled to RT and Et2O (100 mL) was added leading to the precipitation of inorganic salts. After 10 min, the precipitate was filtered-off and the recovered filtrate was concentrated under [20] (50 mg, 0.16 mmol, 1 equiv.) were mixed and dissolved in dry MeCN (2 mL), and K2CO3 was added (27 mg, 0.2 mmol, 1.25 equiv.).…”

Section: Meldrum's Acid-based Pga-sensitive Probe 18mentioning

confidence: 99%

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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

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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Valkyrie Probes: A Novel Class of Enzyme‐Activatable Photosensitizers based on Sulfur‐ and Seleno‐Rosamines with Pyridinium Unit**

Lioret,

Renault,

Maury

et al. 2023

Chemistry An Asian Journal

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The rational design of activatable photosensitizers (aPSs) uncaged by specific disease biomarkers is currently booming due to their positive attributes to achieve targeted photodynamic therapy (PDT). In this context, we present here the synthesis and detailed photophysical characterization of a novel class of hetero‐rosamine dyes bearing sulfur or selenium as bridging heavy atom and 4‐pyridyl meso‐substituent as optically tunable group. The main feature of such photoactive platforms is the spectacular change of their spectral properties depending on the caging/decaging status of their 4‐pyridyl moiety (cationic pyridinium vs. neutral pyridine). The preparation of two alkaline phosphatase (ALP)‐responsive probes (named Valkyrie probes) was achieved through formal N‐quaternarization with 4‐phosphoryloxybenzyl, the traditional recognition moiety for this important diagnostic enzyme. Bio‐analytical validations including fluorescence/singlet oxygen phosphorescence enzyme assays and RP‐HPLC‐fluorescence/‐MS analyses have enabled us to demonstrate the viability and effectiveness of this novel photosensitizer activation strategy. Since sulfur‐containing Valkyrie probe also retains high fluorogenicity in the orange‐red spectral range, this study highlights meso‐pyridyl‐substituted S‐pyronin scaffolds as valuable candidates for the rapid construction of molecular phototheranostic platforms suitable for combined fluorescence diagnosis and PDT.

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Design, synthesis and evaluation of enzyme-responsive fluorogenic probes based on pyridine-flanked diketopyrrolopyrrole dyes

Cited by 6 publications

References 66 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

Valkyrie Probes: A Novel Class of Enzyme‐Activatable Photosensitizers based on Sulfur‐ and Seleno‐Rosamines with Pyridinium Unit**

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