Direct Synthesis of Saturated Alcohols from Conjugated Ketones Using NaBH and Catalytic Amount of CuCN in Ethanol: Additive Catalysis with a Lithium Salt or a Sodium Salt.

A direct, efficient, and highly chemoselective synthesis of saturated alcohols through one-pot sequential 1,4- and 1,2-reduction of cyclic and acyclic conjugated ketones is reported. The saturated alcohols are obtained in very good yields using sodium borohydride (NaBH) as a reducing agent and a catalytic amount of copper(I) cyanide (CuCN) in ethanol as a green solvent. This nontoxic solvent significantly favors full 1,4-reduction, as opposed to methanol.

Light-Induced Unlocking Reactivity of Fragments for Fast Target-Guided Synthesis of Carbonic Anhydrase Inhibitors.

We showcase the successful combination of photochemistry and kinetic target-guided synthesis (KTGS) for rapidly pinpointing enzyme inhibitors. KTGS is a fragment-based drug discovery (FBDD) methodology in which the biological target (BT) orchestrates the construction of its own ligand from fragments featuring complementary reactive functionalities. Notably, fragments interacting with the protein binding sites leverage their spatial proximity, facilitating a preferential reaction.

A Photoredox Thiol-yne Reaction for the Synthesis of Vinyl Sulfide-Based Coumarins and its Effect on Fluorescence Properties.

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.

Do Not Waste Time─Ensure Success in Your Cross-Linking Mass Spectrometry Experiments before You Begin.

Cross-linking mass spectrometry (XL-MS) has become a very useful tool for studying protein complexes and interactions in living systems. It enables the investigation of many large and dynamic assemblies in their native state, providing an unbiased view of their protein interactions and restraints for integrative modeling. More researchers are turning toward trying XL-MS to probe their complexes of interest, especially in their native environments.

The Light-Controlled Release of 2-fluoro-l-fucose, an Inhibitor of the Root Cell Elongation, from a nitrobenzyl-caged Derivative.

Glycan metabolic engineering is a powerful tool for studying the glycosylation in living plant cells. The use of modified monosaccharides such as deoxy or fluorine-containing glycosides has been reported as a powerful pharmacological approach for studying the carbohydrate metabolism. 1,3,4-tri--acetyl-2-fluoro-l-fucose (2F-Fuc) is a potent inhibitor of the plant cell elongation.

Metalloenzyme-Mediated Thiol-Yne Addition Towards Photoisomerizable Fluorescent Dyes.

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.

Novel Approaches in Biomolecule Labeling.

The selective functionalization of biomolecules such as proteins, nucleic acids, lipids or carbohydrates is a focus of persistent interest due to their widespread use, ranging from basic chemical biology research to gain insight into biological processes to the most promising biomedical applications, including the development of diagnostics or targeted therapies [...

3-Benzoylquinoxalinone as a photoaffinity labelling derivative with fluorogenic properties allowing reaction monitoring under "no-wash" conditions.

Described herein is a quinoxalinone-based photoaffinity probe with caged fluorescence properties. Upon visible blue LED irradiation (λ 450 nm), this photo-crosslinker is able to covalently capture proteins with concomitant fluorescence labelling. This process enables monitoring applications under "no wash" conditions.

Tailored Bioorthogonal and Bioconjugate Chemistry: A Source of Inspiration for Developing Kinetic Target-Guided Synthesis Strategies.

Kinetic target-guided synthesis (KTGS) is a promising tool for the discovery of biologically active compounds. It relies on the identification of potent ligands that are covalently assembled by the biological targets themselves from a pool of reagents. Significant effort is devoted to developing new KTGS strategies; however, only a handful of biocompatible reactions are available, which may be insufficient to meet the specificities (stability, dynamics, active site topology, etc.

Fluorophore-Assisted Click Chemistry through Copper(I) Complexation.

The copper-catalyzed alkyne-azide cycloaddition (CuAAC) is one of the most powerful chemical strategies for selective fluorescent labeling of biomolecules in in vitro or biological systems. In order to accelerate the ligation process and ensure efficient formation of conjugates under diluted conditions, external copper(I) ligands or sophisticated copper(I)-chelating azides are used. This latter strategy, however, increases the bulkiness of the triazole linkage, thus perturbing the biological function or dynamic behavior of the conjugates.

Maleimide-based metal-free ligation with dienes: a comparative study.

A brief literature survey reveals that metal-free ligation such as the maleimide-based cycloaddition with electron-rich (hetero)dienes is a widespread tool for the assembly of (bio)molecular systems with applications in biotechnology, materials science, polymers and bio-organic chemistry. Despite their everyday use, only scattered data about their kinetics as well as the stabilities of corresponding products under physiological conditions, are accessible. These key parameters are yet, of paramount importance to ensure the rapid and effective preparation of stable compounds.

Diverted Natural Lossen-type Rearrangement for Bioconjugation through in Situ Myrosinase-Triggered Isothiocyanate Synthesis.

Fluorescein isothiocyanate (FITC) is one of the most extensively used fluorescent probes for the labeling of biomolecules. The isothiocyanate function reacts with lysine residues of proteins to provide a chemically stable thiourea linkage without releasing any byproduct. However, diversification of isothiocyanate-based reagents is still hampered by the lack of mild conditions to generate isothiocyanate chemical functions, as well as by their poor stability and limited solutions available to increase water solubility, restricting the use of isothiocyanate labeling to highly water-soluble fluorophores.

Investigation of tetrazine reactivity towards C-nucleophiles: pyrazolone-based modification of biomolecules.

Chemoselective, biocompatible ligation reactions are the key components for efficient and modular access to biomolecular scaffolds. Tetrazine ligation leads to the formation of a mixture of isomers, which makes reaction monitoring, purification and characterization of conjugates difficult. We report herein a modified tetrazine ligation strategy based on the use of a pyrazolone coupling partner, which provides a single molecule conjugate.

Covalent Modification of Biomolecules through Maleimide-Based Labeling Strategies.

Since their first use in bioconjugation more than 50 years ago, maleimides have become privileged chemical partners for the site-selective modification of proteins via thio-Michael addition of biothiols and, to a lesser extent, via Diels-Alder (DA) reactions with biocompatible dienes. Prominent examples include immunotoxins and marketed maleimide-based antibody-drug conjugates (ADCs) such as Adcetris, which are used in cancer therapies. Among the key factors in the success of these groups is the availability of several maleimides that can be N-functionalized by fluorophores, affinity tags, spin labels, and pharmacophores, as well as their unique reactivities in terms of selectivity and kinetics.

Correction: Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones.

Correction for 'Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones' by Hasan Mtiraoui, et al., Org. Biomol.

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.

Metal-free oxidative ring contraction of benzodiazepinones: an entry to quinoxalinones.

A novel and practical synthesis of 3-benzoylquinoxalin-2(1H)-ones from benzodiazepin-2-ones in two steps from commercially available starting materials is reported. The reaction was achieved in the presence of N-bromosuccinimide in DMSO which served both as a solvent and an oxidant. Significantly, the yet unknown ketone to alcohol fluorescence turn-on of benzoylquinoxalinones was unveiled through the preparation of a fluorescently labelled cholesterol conjugate.

Fluorogenic Behaviour of the Hetero-Diels-Alder Ligation of 5-Alkoxyoxazoles with Maleimides and their Applications.

Fluorogenic reactions are largely underrepresented in the toolbox of chemoselective ligations despite their tremendous potential, particularly in chemical biology and biochemistry. In this respect, we have investigated in full detail the fluorescence behaviour of the azaphthalamide, a scaffold which is generated through a hetero-Diels-Alder reaction of 5-alkoxyoxazole and maleimide derivatives under mild conditions that are compatible with, among others, peptide chemistry. The scope and limitations of such a fluorogenic labelling strategy were examined through four distinct applications, which target enzymatic activities or bioorthogonal reactions.

Readily functionalizable phosphonium-tagged fluorescent coumarins for enhanced detection of conjugates by mass spectrometry.

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.

1,5-Benzodiazepin-2-ones: Investigation of a Family of Photoluminescent Materials.

Photoluminescent materials, that are now ubiquitous in our everyday life, have particularly attracted the attention of the scientific community these past few years due to potential important applications such as in bioimaging, sensing, or optoelectronics. In this context, relatively few different families of molecules have been reported to exhibit fluorescence in the aggregated or solid-state through the excited-state intramolecular proton transfer (ESIPT) photochemical process. The preparation and subsequent determination of photochemical properties of an underexplored family of 1,5-benzodiazepin-2-one derivatives are reported.

New insights into the kinetic target-guided synthesis of protein ligands.

The kinetic target-guided synthesis (KTGS) strategy is an unconventional discovery approach that takes advantage of the presence of the biological target itself in order to irreversibly assemble the best inhibitors from an array of building blocks. This strategy has grown over the last two decades notably after the introduction of the in situ click chemistry concept by Sharpless and colleagues in the early 2000s based on the use of the Huisgen cycloaddition between terminal alkynes and azides. KTGS is a captivating area of research offering an unprecedented and powerful strategy to probe the macromolecular complexity and dynamics of biological targets.

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.

Metal-free decarboxylative hetero-Diels–Alder synthesis of 3-hydroxypyridines: a rapid access to N-fused bicyclic hydroxypiperidine scaffolds.

A complete experimental and theoretical study of the thermally controlled metal-free decarboxylative hetero-Diels–Alder (HDA) reaction of 5-alkoxyoxazoles with acrylic acid is reported. This strategy offers a new entry to valuable 2,6-difunctionalized 3-hydroxypyridines from readily available 2- and 4-disubstituted 5-alkoxyoxazoles. The reaction conditions proved compatible with, among others, ketone, amide, ester, ether, and nitrile groups.

First enzymatic hydrolysis/thio-Michael addition cascade route to synthesis of AChE inhibitors.

The irreversible Michael addition of thiols to acrylamides is reported as a new tool for the kinetic target-guided synthesis. In an unprecedented enzymatic hydrolysis/thio-Michael addition procedure, potent and selective acetylcholinesterase inhibitors are assembled by the enzyme using both its esterasic and templating ability.

Reaction site-driven regioselective synthesis of AChE inhibitors.

The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE.