Synthesis and Photophysical Properties of 4'-5' Disubstituted CinNapht Dyes Accessible through Double SNAr Late-Stage Functionalization.

This article describes the synthesis of a difluorinated CinNapht derivative in the 4' and 5' positions allowing the easy access to two new families of fluorophores by late-stage functionalization using SNAr. The first one comprises derivatives incorporating hindered aromatic amines in the 4' and 5' positions, which show red-emission in apolar solvents. The second one is obtained through the use of dinucleophiles.

A Naphthalimide Based "Turn-ON" Probe for Wash-Free Imaging of Lipid-Droplet in Living Cells With an Excellent Selectivity.

The impacts of dimethylation of 4-Amino-1,8-Naphthalimide (ANI) on its photophysical properties are reported. The resulting 4-DiMe-ANI displays completely different fluorescence properties, conferring it ability to selectively label lipid droplets in living cells. A comprehensive photophysical study revealed that this selectivity arises from an Internal Charge Transfer favored in lipophilic media to the detriment of a non-emissive TICT in more polar media.

CinNapht AIE(E)gens for selective imaging of lipid droplets.

This article describes the synthesis and photophysical properties of Aggregation-Induced Emission (enhancement) luminogens derivated from CinNaphts dyes. These fluorophores can be obtained in good yields in a single SNAr step of a fluorinated CinNapht derivative by incorporating hindered aromatic amines. They exhibit AIE(E) behavior associated with solid-state fluorescence covering an emission range from 563 to 722 nm.

Synthesis of sydnonimines from sydnones and their use for bioorthogonal release of isocyanates in cells.

In this article, we report the synthesis of sydnonimines from sydnones and their use as dipoles for fast click-and-release reactions. The process relies on nucleophilic aromatic substitution of aliphatic and aromatic amines with triflated sydnones. This new methodology allowed the preparation of functionalised sydnonimine probes that are otherwise difficult to prepare.

Visualization of an Endogenous Mitochondrial Azoreductase Activity under Normoxic Conditions Using a Naphthalimide Azo-Based Fluorogenic Probe.

In this paper, we demonstrate the existence of an endogenous mitochondrial azoreductase (AzoR) activity that can induce the cleavage of N═N double bonds of azobenzene compounds under normoxic conditions. To this end, 100% OFF-ON azo-based fluorogenic probes derived from 4-amino-1,8-naphthalimide fluorophores were synthesized and evaluated. The in vitro study conducted with other endogenous reducing agents of the cell, including reductases, demonstrated both the efficacy and the selectivity of the probe for AzoR.

The how and why of naphthalimide/heterocycle-fused hybrid dyes: an overview of the latest developments in the quest for dyes with innovative optical properties.

In this review, a variety of hybrid structures fusing aromatic heterocycles of different natures to a naphthalimide backbone are discussed. This strategy constitutes an efficient approach to generate original structures displaying singular photophysical properties and thus offering new perspectives in the fields of fluorogenic detection, optoelectronics, and photodynamic therapy. In this review, different synthetic approaches and structures reported in the literature are discussed.

Unprecedented perspectives on the application of CinNapht fluorophores provided by a "late-stage" functionalization strategy.

A simple and easy-to-implement process based on a nucleophilic aromatic substitution reaction with a wide variety of nucleophiles on a fluorinated CinNapht is described. This process has the key advantage of introducing multiple functionalities at a very late stage, thus providing access to new applications including the synthesis of photostable and bioconjugatable large Stokes shift red emitting dyes and selective organelle imaging agents, as well as AIEE-based wash-free lipid droplet imaging in live cells with high signal-to-noise ratio. The synthesis of bench-stable CinNapht-F has been optimized and can be reproduced on a large scale, making it an easy-to-store starting material that can be used at will to prepare new molecular imaging tools.

Fast and Bioorthogonal Release of Isocyanates in Living Cells from Iminosydnones and Cycloalkynes.

Bioorthogonal click-and-release reactions are powerful tools for chemical biology, allowing, for example, the selective release of drugs in biological media, including inside animals. Here, we developed two new families of iminosydnone mesoionic reactants that allow a bioorthogonal release of electrophilic species under physiological conditions. Their synthesis and reactivities as dipoles in cycloaddition reactions with strained alkynes have been studied in detail.

Expansion of the Strigolactone Profluorescent Probes Repertory: The Right Probe for the Right Application.

Strigolactones (SLs) are intriguing phytohormones that not only regulate plant development and architecture but also interact with other organisms in the rhizosphere as root parasitic plants (, and ) and arbuscular mycorrhizal fungi. Starting with a pioneering work in 2003 for the isolation and identification of the SL receptor in parasitic weeds, fluorescence labeling of analogs has proven a major strategy to gain knowledge in SL perception and signaling. Here, we present novel chemical tools for understanding the SL perception based on the enzymatic properties of SL receptors.

"CinNapht" dyes: a new cinnoline/naphthalimide fused hybrid fluorophore. Synthesis, photo-physical study and use for bio-imaging.

Six-membered-diaza ring of cinnoline has been fused on naphthalimide dye to give a donor-acceptor system called CinNapht. This red shifted fluorophore, that can be synthesised in gram scale, exhibits a large Stoke shift and a fluorescence quantum yield up to 0.33.

Carbon isotope labeling of carbamates by late-stage [C], [C] and [C]carbon dioxide incorporation.

A general procedure for the late-stage [11C], [13C] and [14C]carbon isotope labeling of cyclic carbamates is reported. This protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a direct, cost-effective and sustainable manner. A disconnection/reconnection strategy, involving ring opening/isotopic closure, was also implemented.

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

A simple and effective biocompatible domino reaction triggered by a model protease and leading to the formation of strongly fluorescent quinoxalin-2(1)-one -heterocycles is described. Some positive attributes including versatility and the 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 probe in the fields of sensing and bioimaging.

Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO.

A robust, click-chemistry-inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes ( C, C, C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems.

An optimized procedure for direct access to 1-indazole-3-carboxaldehyde derivatives by nitrosation of indoles.

Indazole derivatives are currently drawing more and more attention in medicinal chemistry as kinase inhibitors. 1-indazole-3-carboxaldehydes are key intermediates to access to a variety of polyfunctionalized 3-substituted indazoles. We report here a general access to this motif, based on the nitrosation of indoles in a slightly acidic environment.

Is the EuroSCORE II reliable to estimate operative mortality among octogenarians?

Objectives: Concerns have been raised about the predictive performance (PP) of the EuroSCORE I (ES I) to estimate operative mortality (OM) of patients aged ≥80. The EuroSCORE II (ES II) has been described to have better PP of OM but external validations are scarce. Furthermore, the PP of ES II has not been investigated among the octogenarians.

A miniaturized peptidyl-prolyl isomerase enzyme assay.

Prolyl-peptidyl isomerases (PPIases) are enzymes that are found in all living organisms. They form an essential part of the cellular protein folding homeostasis machinery. PPIases are associated with many important human diseases, e.

Total Synthesis and Structural Revision of Chaetoviridins A.

The first synthesis of the proposed structures of chaetoviridins A 1-4 has been achieved in 10 steps by controlling the syn- or anti-aldol side chain. The angular lactone has been regioselectively introduced by condensation of a chiral dioxin-4-one to cazisochromene. Comparison of the NMR and circular dichroism data of the synthesized and reported natural products led to the complete reassignment and renaming of the chaetoviridins.

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A.

In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines.

Azo-Based Fluorogenic Probes for Biosensing and Bioimaging: Recent Advances and Upcoming Challenges.

The use of nonfluorescent azo dyes as dark quenchers in activatable optical bioprobes based on the Förster resonance energy transfer (FRET) mechanism and designed to target a wide range of enzymes has been established for over two decades. The key value of the azo moiety (-N=N-) to act as an efficient "ON-OFF" switch of fluorescence once introduced within the core structure of conventional organic-based fluorophores (mainly fluorescent aniline derivatives) has recently been exploited in the development of alternative reaction-based small-molecule probes based on the "profluorescence" concept. These unprecedented "azobenzene-caged" fluorophores are valuable tools for the detection of a wide range of reactive (bio)analytes.

Influence of substituent heteroatoms on the cytoprotective properties of pyrimidinol antioxidants.

Recently, we described the optimization of novel pyrimidinol-based antioxidants as potential therapeutic molecules for targeting mitochondrial diseases. That study focused on improving the potency and metabolic stability of pyrimidinol antioxidants. This led us to consider the possibility of altering the positions of the exocyclic alkoxy and alkylamino substituents on the pyrimidinol scaffold.

Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability.

Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism.

Mitochondrial Nitroreductase Activity Enables Selective Imaging and Therapeutic Targeting.

Nitroreductase (NTR) activities have been known for decades, studied extensively in bacteria and also in systems as diverse as yeast, trypanosomes, and hypoxic tumors. The putative bacterial origin of mitochondria prompted us to explore the possible existence of NTR activity within this organelle and to probe its behavior in a cellular context. Presently, by using a profluorescent near-infrared (NIR) dye, we characterize the nature of NTR activity localized in mammalian cell mitochondria.

Selective Functionalization of Antimycin A Through an N-Transacylation Reaction.

Acylation of 3-(N-formylamino)salicylic acids resulted in transacylation with loss of the formyl moiety. The reaction proceeds through a bis-N-acylated intermediate, which undergoes facile deformylation. This transacylation reaction has been employed for the site-specific functionalization of the mitochondrial poison antimycin A, affording several novel derivatives.

Azobenzene-caged sulforhodamine dyes: a novel class of 'turn-on' reactive probes for hypoxic tumor cell imaging.

New sulforhodamine-based fluorescent 'turn-on' probes have been developed for the direct imaging of cellular hypoxia. Rapid access to this novel class of water-soluble 'azobenzene-caged' fluorophores was made possible through an easily-implementable azo-coupling reaction between a fluorescent primary arylamine derived from a sulforhodamine 101 scaffold (named SR101-NaphtNH ) and a tertiary aniline whose N-substituents are neutral, cationic, or zwitterionic. The detection mechanism is based on the bioreductive cleavage of the azo bond that restores strong far-red fluorescence (emission maximum at 625 nm) by regenerating the original sulforhodamine SR101-NaphtNH .

Kondrat'eva ligation: Diels-Alder-based irreversible reaction for bioconjugation.

Diversification of existing chemoselective ligations is required to efficiently access complex and well-defined biomolecular assemblies with unique and valuable properties. The development and bioconjugation applications of a novel Diels-Alder-based irreversible site-specific ligation are reported. The strategy is based on a Kondrat'eva cycloaddition between bioinert and readily functionalizable 5-alkoxyoxazoles and maleimides that readily react together under mild and easily tunable reaction conditions to afford a fully stable pyridine scaffold.