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Article Dans Une Revue Organic Letters Année : 2020

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

Résumé

A simple and effective biocompatible domino reaction triggered by a model protease and leading to formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and ability to provide outstanding fluorescence "OFF-ON" responses were revealed by this work. They open the way for practical applications of this novel type of "covalent-assembly" based fluorescent probes in the fields of sensing and bioimaging. Among the myriad of synthetic transformations and catalysts currently available for concise and efficient synthesis of organic molecules, bioinspired approaches based on the use of enzymes often intertwined with cascade/domino processes, occupy a special place and are receiving greater attention of late. 1 They have also contributed to the emergence of in vivo chemistry (often named as intracellular chemistry) 2 that can be defined as the use of living cells as reaction vessels and their constituents (e.g., enzymes) possibly together with abiotic metal catalysts, 3 to achieve one or several reactions for internal construction of sophisticated nano-objects from exogenous synthetic precursors. In addition to possible applications devoted to the production of high-value chemicals, one of the most striking achievements in this emerging area is undoubtedly the biocompatible "click" reaction between an aromatic nitrile (e.g., 6-amino-2-cyanoben-zothiazole (CBT)) and D-cysteine leading to D-luciferin scaffold , 4 discovered by the Rao group in 2010 (Figure 1, top). 5 Its ability to be effective for the controlled assembly of nanoparti-cles in living cells together with its possible triggering by a bio-stimulus (pH, redox status and/or hydrolytic enzymes) has fostered the emergence of cutting-edge reactivity-based sensing approaches for in vivo molecular imaging, especially through the bioluminescence modality, for addressing challenges associated to light-based diagnosis. 6 These remarkable achievements perfectly illustrate both utility and benefits of biocompatible/bioorthogonal transformations that are capable of generating a bright luminescence output signal upon the action of a biological trigger. In the field of activity-based fluorescent sensing, a new probe design principle namely the "covalent-assembly" approach, pioneered by the Swager group with the design of a "smart" semiconduc-tive polymer for fluorogenic detection of fluoride ions, 7 and next rationalized by Anslyn and Yang to address relevant biological questions, 8,9 has emerged in the mid-2000s. This cutting edge strategy is based on in situ formation of a fluorophore from a caged compound (not belonging to major classes of fluorescent dyes and, in theory at least, devoid of light emission ability) through a domino reaction triggered by the species to be detected and ideally designed to work properly in aqueous media (Figure 1, middle and bottom). Since this novel class of ac-tivatable fluorescent probes are supposed to dramatically improve signal-to-noise ratio (S/N) responses, thus providing optimal detection sensitivity, it is not really surprising that they have rapidly become popular tools for specific detection and imaging of enzyme activities (mainly, hydrolases and reduc-tases). The vast majority of "covalent-assembly" based fluorescent probes devoted to enzyme biosensing involve in situ formation of blue-green emitting (2-imino)coumarins or related fluorophores through analyte-triggered lactonization or Pinner cyclization reactions 10,11,12 even if some of these published examples are also regarded as fluorogenic probes undergoing ri-gidification of their floppy pre-existing push-pull system upon the action of the bioanalyte. 8b Our group, inspired by work of Yang et al., 13 have recently contributed to this research field by expanding the scope to longer-wavelength fluorophores belonging to the popular class of xanthene dyes (i.e., unsymmetrical pyronins with fluorescence features within the yellow-orange spectral region). 14 Some notable results were obtained with

Domaines

Chimie organique
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Dates et versions

hal-03006821 , version 1 (17-11-2020)

Identifiants

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Garance Dejouy, Kévin Renault, Quentin Bonnin, Arnaud Chevalier, Cédric Michaudet, et al.. Fluorogenic Enzyme-Triggered Domino Reactions Producing Quinoxalin-2(1H)-one-based Heterocycles. Organic Letters, 2020, 22 (16), pp.6494-6499. ⟨10.1021/acs.orglett.0c02287⟩. ⟨hal-03006821⟩
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