Designing New Natural-Mimetic Phosphatidic Acid: A Versatile and Innovative Synthetic Strategy for Glycerophospholipid Research Antoine Schlichter, Alexander Wolf, Thomas Ferrand, Aurelien Cocq, Lina Riachy, et al. Angewandte Chemie International Edition, 2025 Glycerophospholipids (GPLs) play important roles in cellular compartmentalization and signaling. Among them, phosphatidic acids (PA) exist as many distinct species depending on acyl chain composition, each one potentially displaying unique signaling function. Although the signaling functions of PA have already been demonstrated in multiple cellular processes, the specific roles of individual PA species remain obscure due to a lack of appropriate tools. Indeed, current synthetic PA analogues fail to preserve all the functions of natural PA. To circumvent these limitations, we developed a novel synthetic approach to produce PA analogues without compromising structural integrity of acyl chains. Moreover, addition of a clickable moiety allowed flexible grafting of different molecules to PA analogues for various biological applications. Hence, this innovation also provides powerful tools to investigate specific biological activities of individual PA species, with potential applications in unraveling complex GPL‐mediated signaling pathways.
Oxidative Neutralisation of Sulfur-Based Chemical Warfare Agents Mediated by a Lipase: From Batch to Flow Reactor Maxime Boddaert, Valmir Baptista da Silva, Sergui Mansour, Daniela Vuluga, Pierre‐Yves Renard, et al. Chemistry A European Journal, 2025 The sulfur‐containing chemical warfare agents sulfur mustard HD and nerve agent VX are highly toxic and persistent in the environment. Therefore, their neutralisation requires harsh oxidation conditions, but also precise selectivity. Here we report the safe and effective detoxification of surrogates CEES and PhX by selective oxidation of the sulfur atom by generating peracetic acid from AcOEt and aq. H2O2 assisted by the supported lipase CALB. Morever, it is possible to perform these neutralisations with safe ‘on demand’ generation of AcOOH in a flow system by using a packed bed reactor containing the supported biocatalyst.
Light-Induced Unlocking Reactivity of Fragments for Fast Target-Guided Synthesis of Carbonic Anhydrase Inhibitors Chloé Puteaux, Isabelle Toubia, Lina Truong, Marie Hubert‐Roux, Laetitia Bailly, et al. Angewandte Chemie International Edition, 2024 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. Consequently, the resulting bivalent ligand exhibits heightened affinity. Within the realm of KTGS strategies, in situ click chemistry stands out as the most widely used to identify potent protein binders. This approach requires significant protein contributions, such as binding interactions and appropriate orientations of fragments, to overcome high activation barriers. This leads to prolonged incubation times and the potential for generating false negatives, thereby limiting this strategy to proteins that are stable enough in buffer. We herein unveil the possibility to integrate photochemistry into the realm of KTGS, accelerating the ligation reaction between fragments to a time scale of minutes. This approach should significantly expand the narrow reactivity window of traditional KTGS reactions, paving the way for the exploration and development of novel photo‐KTGS reactions.
A Photoredox Thiol-yne Reaction for the Synthesis of Vinyl Sulfide-Based Coumarins and its Effect on Fluorescence Properties Isabelle Toubia, Chloé Puteaux, Karolina Weronika Swiderska, Marie Hubert‐Roux, Pierre‐Yves Renard, et al. Chemistry A European Journal, 2024 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.
Detoxification of V-Nerve Agents Assisted by a Microperoxidase: New Pathway Revealed by the Use of a Relevant VX Simulant Valmir Baptista da Silva, Jean‐Pierre Mahy, Xavier Brazzolotto, Pierre‐Yves Renard, Rémy Ricoux, et al. Chembiochem, 2024 The biocatalyzed oxidative detoxification of the V‐series simulant PhX, by mean of the microperoxidase AcMP11, affords the corresponding phosphonothioate as the prominent product instead of the classical P−S and P−O bond cleavage. While PhX is structurally very close to the live agent VX (the methyl group is replaced by a phenyl), assessment with other surrogates missing the nucleophilic amino function displayed more resistance under the same conditions with no phosphonothioate observed. These encouraging results highlight 1) the efficacy of AcMP11 microperoxidase to efficiently detoxify V‐series organophosphorus nerve agents (OPNA), and 2) the necessity to use representative alkyl or aryl phosphonothioates simulants such as PhX bearing the appropriate side chain as well as the P−O and P−S cleavable bond to mimic accurately the V‐series OPNA to prevent false positive or false negative results.
Easy access to phosphonothioates Pierre-Yves Renard, Hervé Schwebel, Philippe Vayron, Ludovic Josien, Alain Valleix, et al. Chemistry A European Journal, 2002
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