Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222

2′-Modified thymidines with bioorthogonal cyclopropene or sydnone as building blocks for copper-free postsynthetic functionalization of chemically synthesized oligonucleotides

International audienceThe development of facile methods for conjugating relevant probes, ligands, or delivery agents onto oligonucleotides (ONs) is highly desirable both for fundamental studies in chemical biology and for improving the pharmacology of ONs in medicinal chemistry. Numerous efforts have been focused on the introduction of bioorthogonal groups onto phosphoramidite building blocks, allowing the controlled chemical synthesis of reactive ONs for postsynthetic modifications. Among these building blocks, alkyne, cyclooctynes, trans-cyclooctene, and norbornene have been proved to be compatible with automated solid-phase chemistry. Herein, we present the development of novel 2′-functionalized nucleoside phosphoramidite monomers comprising bioorthogonal methylcyclopropene or sydnone moieties and their introduction for the first time to ON solid-phase synthesis. Traceless ON postsynthetic modifications with reactive complementary probes were successfully achieved through either inverse electron-demand Diels–Alder (iEDDA) reactions or strain-promoted sydnone–alkyne cycloaddition (SPSAC). These results expand the set of bioorthogonal phosphoramidite building blocks to generate ONs for postsynthetic labeling

Charge density of a putative intermediary product in the total synthesis of the cephalotaxine

International audienceA high resolution diffraction measurement have been performed on a putative precursor of cephalotaxine; using a Brücker CCD detector. The compound crystallizes in P21/n space group (V = 1174.49(2) Å-3). 161121 reflections were collected leading to 10690 independent reflections up to 1,11 Å-1 (Rint = 0,0215). Multipole refinement (Hansen and Coppens model [1]) converges with reliability factors (R(F) = 0,0283 and GOF = 1,32). Electron deformation maps show up a strong delocalization over the four cycles. The calculation of the atomic net charges deduced from a k refinement are in agreement with the reactivity (or the non-reactivity) of the compound. The topological properties at the bond critical points (3,-1) are reported and are also in a quite good agreement with the chemistry. Finally the electrostatic potential has been calculated [2] and two different representations are used in order to characterize the compound: 3D isopotential surfaces, and 3D isodensity molecular surface colored by the electrostatic potential (figure). [1] Hansen N. Coppens P.

Crystallographic/experimental electron density characterizations and reactions with nucleophiles of β-enaminonitriles possessing a pyrrolobenzazepine core

International audienceIn connection with a total synthesis of cephalotaxine (1a), we have examined the addition of various nucleophilic reagents to [ABC] subunits 2 and 7 possessing a pyrrolobenzazepine core. In fact, this reaction implicates invariably the carbonyl group of 2. Regarding the reaction of 7 with nucleophiles, the most striking aspect is the complete lack of reactivity of the enaminonitrile moiety. For instance, the condensation of 7 with methylmagnesium bromide involves exclusively the cleavage of the dioxole ring, yielding regioisomers 9 and 10. With the aim of understanding the unexpected reactivity of 2 and 7 toward nucleophiles, crystallographic studies of 2 and 7 and an experimental electron density determination of 7 were carried out. The marked reactivity of the carbonyl group of 2 was interpreted by invoking the weakness of the amide resonance, due to a pronounced delocalization of the N9 lone pair over the enaminonitrile moiety. The electron density study of 7 reveals this electron delocalization along the enaminonitrile fragment, highlighted and quantified through the bond geometries, topological indicators, and atomic charges, a phenomenon that is responsible for the failure of the addition of nucleophilic species

Apports de la diffraction des rayons X et de la densité électronique expérimentale à l’étude d’intermédiaires de synthèse de la céphalotaxine

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Charge density of a putative synthetic intermediate in the total synthesis of the cephalotaxine

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