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Fluorescent coumarins are an important class of small-molecule organic fluorophores ubiquitous in different well-established and emerging fields of research including, among others, biochemistry and chemical biology. The present work aims at covering the poor detectability of coumarin-based conjugates by mass spectrometry while keeping important photophysical properties of the coumarin core. In this context, the synthesis of readily functionalizable phosphonium-tagged coumarin derivatives enabling a dual mass-tag and fluorescence labelling of analytes or (bio)molecules of interest through a single-step protocol, is reported. The utility of these coumarins is illustrated through the preparation of fluorogenic substrates that facilitated identification of the peptide fragment released by specific proteolytic cleavages.

Members of a series of boron difluoride complexes with 3-(heteroaryl)-2-iminocoumarin ligands bearing both a phenolic hydroxyl group (acting as a fluorogenic center) and an N-aryl substituent (acting as a stabilizing moiety) have been synthesized in good yields by applying a straightforward two-step method. These novel fluorogenic dyes belong to the family of "Boricos" (D. Frath et al., Chem. Commun.- 2013, 49, 4908-4910) and are the first examples of phenol-based fluorophores of which the photophysical properties in the green-yellow spectral range are dramatically improved by N,N-chelation of a boron atom. Modulation of their fluorescence properties through reversible chemical modification of their phenol moieties has been demonstrated by the preparation of the corresponding 2,4-dinitrophenyl (DNP) ethers, which led to a dramatic "OFF-ON" fluorescence response upon reaction with thiols. Additionally, to expand the scope of these "7-hydroxy-Borico" derivatives, particularly in biolabeling, amine or carboxylic acid functionalities amenable to (bio)conjugation have been introduced within their scaffold. Their utility has been demonstrated in the preparation of fluorescent bovine serum albumin (BSA) conjugates and "Borico"-DOTA-like scaffolds in an effort to design novel monomolecular multimodal fluorescence- radioisotope imaging agents., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Coumarins still remain one of the most widely explored fluorescent dyes, with a broad spectrum of applications spanning various fields, such as molecular imaging, bioorganic chemistry, materials chemistry, or medical sciences. Their fluorescence is strongly based on a push‐pull mechanism involving an electron‐donating group (EDG), mainly located at the C7 or C8 positions of the dye core. Unfortunately, up to now, these positions have been very limited to hydroxyl or amino groups. In this study, we present in detail the synthesis of the first series of coumarins bearing a vinyl sulfide as the EDG at the C7 position. These derivatives were prepared by thiol‐yne reaction, promoted by ruthenium‐ or porphyrin‐based photoredox catalysis, enabling rapid late‐stage diversification. We also functionalized coumarins with short peptides, and BSA protein as a proof‐of‐concept study, in a single‐step process. This strategy, capable of proceeding under aqueous conditions, overcomes the protection/deprotection steps usually required by traditional methods, which also use strong bases and organic solvents. Moreover, the photophysical properties such as absorption and emission of obtained coumarins (for 3‐CF3, 3‐benzothiazole, 6–8‐difluoro derivatives), predominantly exhibited large Stokes shifts (up to 204 nm) and maintained intramolecular charge transfer (ICT) characteristics. [ABSTRACT FROM AUTHOR]

The constant need for high‐performance aniline‐ or phenol‐based fluorophores suitable for the construction of activity‐based fluorescent probes, led us to study both synthesis and photophysics of C3‐N‐methylpyridinium‐4‐yl substituted 7‐(dialkylamino)/7‐hydroxycoumarins. Indeed, in the field of photoactive organic molecules, the positively charged N‐alkylpyridinium‐4‐yl groups are often used as acceptor units to dramatically impact spectral features through promoting intramolecular charge transfer (ICT) processes. They are also known as effective water‐solubilizing and mitochondria targeting moieties. The poor fluorescence efficiency of cationic 7‐hydroxycoumarin derivatives in aqueous physiological conditions was highlighted and rationalized by the predominance of a neutral quinonoid form in such buffer medium. The ability of the excited singlet state (S1) of this neutral species to undergo intersystem crossing (ISC) to triplet state (T1) was partly supported by phosphorescence measurements of singlet oxygen. We also took advantage of green‐emissive properties of 7‐(diethylamino)‐3‐(N‐methylpyridinium‐4‐yl)coumarin to successfully design and validate a novel small‐molecule fluorescent probe for the detection of alkaline phosphatase (ALP), based on the "covalent‐assembly" principle. A practical use of ortho‐formylated 7‐hydroxy‐3‐(N‐methylpyridinium‐4‐yl)coumarin was next considered with the synthesis of a Fe(III)‐salen complex whose the potential as a "molecular disassembly" probe for fluorogenic sensing of pyrophosphate (PPi) anion was assessed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Proteins are able to irreversibly assemble biologically active ligands from building blocks bearing complementary reactive functions due their spatial proximity, through a kinetic target‐guided synthetic process (also named in situ click chemistry). Although linkages thus formed are mostly passive, some of them have shown to significantly contribute to the protein binding through for instance hydrogen bonding and stacking interactions. Biocompatible reactions and click chemistry are a formidable source of inspiration for developing such new protein‐directed ligations. This study reports a proximity‐induced thiol‐yne synthesis of carbonic anhydrase inhibitors. Not only this example widens the arsenal of kinetic target‐guided synthesis (KTGS) eligible reactions, but the obtained product displayed unsuspected photophysical properties. The corresponding vinyl sulfide linkage conjugated to a coumarin core proved to be engaged in a monodirectional Z to E photoisomerization process. Further investigations guided by theoretical calculations showed that fine‐tuning of the nature of the substituents on the coumarin moiety allows to obtain a bidirectional photochemical process, thus discovering a new photoswitching moiety, displaying moreover fluorescence properties. Due to the spectral tunability of coumarin derivatives, this work should open new opportunities for the design of vinyl sulfide‐based photoswitch systems with modular photophysical properties. [ABSTRACT FROM AUTHOR]

Non‐protein thiols such as GSH, Hcy, or Cys, are present at different concentration levels in the body depending on the thiol species and their localization (plasma, cell, urine etc···). They play vital roles in controlling redox‐mediated biological processes, and abnormal levels of biothiols are related to a variety of syndromes. In few years, fluorometric methods have gain increasing attention enabling a rapid, sensitive and spatiotemporal detection of biothiols. Herein, is reported a novel two‐step access to a water‐soluble fluorogenic probe based on the 7‐aminocoumarin dye conjugated to a pyrazolone moiety. Upon the addition of biothiols, the fluorescence is turned‐on at 485 nm by a reversible thio‐Michael addition process, which enables the detection of biothiols in the low nanomolar range. A novel and water‐soluble pyrazolone‐coumarin‐based probe for the fluorogenic detection of thiols is reported. The sensing mechanism of this probe involves a rapid and reversible thiol‐Michael addition. [ABSTRACT FROM AUTHOR]

A straightforward method to synthesize 3-(2-benzimidazolyl)-7-hydroxycoumarins, based on the condensation reaction of 7-acetoxy-3-formylcoumarin with various C- and/or N-substituted ortho-phenylenediamine derivatives is presented. This unusual approach proved particularly effective for introducing different hydrophilic groups (carboxylic or sulfonic acids or trimethylalkylammonium moieties) onto the heteroaryl scaffold, leading to cyan-green emitting coumarins that were both water-soluble and strongly fluorescent under physiological conditions. The further extension of this condensation reaction to bis(2-aminophenyl)diselenide enabled the first synthesis of 3-(2-benzoselenazolyl)-7-hydroxycoumarin. The potential utility of these new 7-hydroxycoumarins was demonstrated through the synthesis and spectroscopic and analyte-responsive behavior of fluorogenic probes suitable for sensing biologically relevant thiols and urokinase, a protease that plays a key role in cancer invasion and metastasis. [ABSTRACT FROM AUTHOR]

The synthesis and photophysical properties of novel water-soluble phenol-based fluorophores derived from 3-benzothiazolyl-7-hydroxycoumarin and emitting in the range 485–631 nm are described. Further conversion into thiol-sensitive fluorogenic probes through the chemical modification of their hydroxyl group was next investigated. Depending on the type of thiol-reactive quenching moiety used (2,4-dinitrobenzenesulfonyl ester, 2,4-dinitrophenyl ether or benzoquinone-type Michael acceptors) and the water-solubilizing group(s) pre-introduced into the coumarin core, dramatic differences in the thiol-induced fluorescence activation of these pro-fluorophores under physiological conditions were observed. Results for this comparative study provide valuable informations for the selection of the most suitable structural features for designing 7-hydroxycoumarin-based long-wavelength fluorescent probes for thiol bioimaging. [ABSTRACT FROM AUTHOR]

An efficient synthesis of water-soluble unsymmetrical sulforhodamine/sulforhodol fluorophores containing a single julolidine fragment is presented. Owing to their valuable spectral properties in aqueous buffers, these dyes, especially those bearing a free aniline or phenol moiety, are valuable components of fluorogenic probes for a variety of biosensing applications. A further extension of this synthetic methodology to unusual phenols, namely 7- N, N-dialkylamino-4-hydroxy coumarins has enabled us to provide a new family water-soluble dyes of large Stokes' shift with far-red spectral features. [ABSTRACT FROM AUTHOR]

• Friedel-Crafts alkylation of 4-(diethylamino)salicylaldehyde was achieved. • Two novel 8-substituted 7-(diethylamino)coumarin dyes were synthesized. • These benzyl-substituted coumarin fluorophores exhibit remarkable AIE properties. An unprecedented C-3 functionalization of 4-(diethylamino)salicylaldehyde through a Friedel-Crafts type alkylation reaction has been discovered during the synthesis of "covalent-assembly"-based fluorescent probes for detection of fluoride ions. The resulting Friedel-Crafts adduct was successfully used for the preparation of two novel 8-substituted 7-(diethylamino)coumarin dyes. The photophysical study of these fluorophores has enabled us to highlight their remarkable aggregation-induced emission (AIE) properties characterized by a yellow-orange emission of aggregates in water. Therefore, 4-(tert -butyldimethylsilyloxy)benzyl substituent was identified as a novel AIE-active moiety which could be seen as a possible alternative to popular tetraphenylethylene (TPE). [ABSTRACT FROM AUTHOR]

An expedient synthesis of the first examples of iron-carbonyl complex–coumarin conjugates is reported. 7-Amino/7-hydroxycoumarin derivatives have been readily derivatized through an easily implemented single-step reaction involving the tricarbonyl(η 5 -cyclohexadienyl)iron(1+) cation [(C 6 H 7 )Fe(CO) 3 ] + . The scope and limitations of this N -/ O -alkylation reaction were also investigated. The fluorescence properties of these novel metal–carbonyl complexes have been studied and support their further use as valuable building blocks in the design of bimodal contrast agents for combined vibrational and fluorescence imaging. [ABSTRACT FROM AUTHOR]

A FRET-based fluorescent probe for the detection of sulfide and/or sulfite in aqueous buffer, was constructed by connecting the quencher moiety nitrobenzofurazan (7-nitro-1,2,3-benzoxadiazole, NBD) to a water-soluble 3-(2-benzimidazolyl)-7-hydroxycoumarin carboxylic acid through a piperazine linker. This probe exhibits good selectivity and high sensitivity for sulfite and sulfide over cysteine and other potential analytes. Furthermore, this is one of the few examples of fluorogenic coumarins whose solubility in water is maintained upon its conversion into reaction-based fluorescent probes. [ABSTRACT FROM AUTHOR]

Abstract: A versatile methodology for the synthesis of 6/8-halogenated 7-aminocoumarins from the corresponding 7-hydroxy analogs using Pd-catalyzed amination reaction as the key step is presented. Further readily conversion into 7-azidocoumarins was performed and the resulting aryl azides proved higher stability and reactivity than the corresponding non-halogenated parent compound. These new compounds may thus constitute attractive scaffolds for designing novel photoaffinity reagents for various challenging bio-labeling applications. [Copyright &y& Elsevier]