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Asma Bourafai-Aziez,1 Mohammed Benabderrahmane,2 Hippolyte Paysant,3,4 Louis-Bastien Weiswald,3,4 Laurent Poulain,3,4 Ludovic Carlier,5 Delphine Ravault,5 Marie Jouanne,2 Gaël Coadou,1 Hassan Oulyadi,1 Anne-Sophie Voisin-Chiret,2 Jana Sopková-de Oliveira Santos,2 Muriel Sebban1 1Normandie Université, UNIROUEN, INSA de Rouen, CNRS Laboratoire COBRA (UMR 6014 & FR 3038), Rouen, 76000, France; 2Normandie Univ, UNICAEN, CERMN, Caen, 14000, France; 3Normandie Université, UNICAEN, Inserm U1086 ANTICIPE «Interdisciplinary Research Unit for Cancer Prevention and Treatment», Biology and Innovative Therapeutics for Ovarian Cancers Group (BioTICLA), Centre de Lutte Contre le Cancer F. Baclesse, Caen, 14076, France; 4UNICANCER, Centre de Lutte Contre le Cancer F. Baclesse, Caen, 14076, France; 5Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, Paris, FranceCorrespondence: Muriel SebbanNormandie Université, UNIROUEN, INSA de Rouen, CNRS Laboratoire COBRA (UMR 6014 & FR 3038), Rouen, 76000, France, Tel +33 2 35 52 29 44Fax +33 2 35 52 24 41Email muriel.sebban@univ-rouen.frJana Sopková-de Oliveira SantosNormandie Univ, UNICAEN, CERMN, Caen, 14000, FranceTel +33 2 31 56 68 21Fax +33 2 31 56 68 03Email jana.sopkova@unicaen.frIntroduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1.Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234.Conclusion: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.Keywords: drug repurposing, Mcl-1, Deferasirox, NMR, docking, dynamics

The measurement of small homonuclear 2J7Li–7Li scalar couplings relying on constant time (CT) COSY NMR suffers from strong time limitations. We describe the first Ultrafast CT COSY experiment on lithium 7, which provides a considerable acceleration in the study of the aggregation state and dynamics of n-BuLi/MeLi complexes. [ABSTRACT FROM AUTHOR]

Determination of the structure and solvation states of organolithium aggregates in complex solution remains a challenging task. Here, we show that 1H Pure Shift DOSY NMR provides better resolution spectra without overlapping, even for complex solutions of mixed aggregates of n-BuLi/n-BuOLi. This ensures the direct observation of the apparent diffusion constant for each component in the solution and therefore allows a fast assignment of aggregation states, and solvation degree. [ABSTRACT FROM AUTHOR]

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., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

In this paper, we investigate the secondary structure of the Piv-Pro-d-Ser-NHMe peptide by means of nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) experiments, in conjunction with theoretical simulations based on molecular dynamics and time-dependent density functional theory calculations including polarizable embedding to account for solvent effects. The various experimental and theoretical protocols are assessed and validated, and are shown to provide a consistent description of the turn structure adopted by this peptide in solution. In addition, a simple fitting procedure is proposed to make the simulated and experimental ECD almost perfectly match. This full methodology is finally tested on another small peptide, enlightening its efficiency and robustness.

Large amounts of root exudates are released by plant roots into the soil. Due to their importance in regulating the rhizosphere properties, it is necessary to unravel the precise composition and function of exudates at the root-soil interface. However, obtaining root exudates without inducing artefacts is a difficult task. To analyse the low molecular weight molecules secreted by pea roots, a protocol of root exudate collection was developed to perform a metabolomics analysis using Nuclear Magnetic Resonance (NMR). To date a few NMR studies are dedicated to root exudates. Plant culture, exudates collection and sample preparation methods had thus to be adapted to the NMR approach. Here, pea seedlings were hydroponically grown. The obtained NMR fingerprints show that osmotic stress increases the quantity of the exudates but not their diversity. We therefore selected a protocol reducing the harvest time and using an ionic solvent and applied it to the analysis of faba bean exudates. NMR analysis of the metabolic profiles allowed to discriminate between pea and faba bean according to their exudate composition. This protocol is therefore very promising for studying the composition of root exudates from different plant species as well as their evolution in response to different environmental conditions or pathophysiological events., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This work shows why it is imperious to use an excess of butyllithium for a directed ortho-lithiation of a trifluoromethyl sulfoximine. The analysis of mixtures of n-BuLi and sulfoximine 1 in THF-d 8 using { 1 H, 6 Li, 13 C, 15 N, 19 F} NMR experiments at low temperatures reveal that a first deprotonation occurs that leads to dimeric and tetrameric N-lithiated sulfoximine (93 : 7). Using an excess n-BuLi (5 equivalents), the second deprotonation on the ortho-position of the aromatic occurs. Six species were observed and characterized on the way. It includes three aggregates involving a sulfoximine: i) a [dilithiated sulfoximine/(n-BuLi)] dimer solvated by four molecules of THF (Agg2, 39 %); ii) a [dilithiated sulfoximine/(n-BuLi) 3 ] tetramer solvated by six molecules of THF (Agg3, 39 %); iii) a [dilithiated sulfoximine/(n-BuOLi) 3 ] tetramer solvated by four molecules of THF (Agg1, 22 %). A DFT study afforded optimized solvated structures for all these aggregates, fully consistent with the NMR data., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Simple nitroarenes such as nitronaphthalenes and nitroquinolines smoothly undergo dearomatizing [4+2] cycloadditions with silyloxydienes under 16 kbar. Highly functionalized 3-dimensional polycyclic adducts bearing a tetrasubstituted carbon centre at the ring junction are obtained in one step from simple raw materials. This unprecedented dearomative Diels-Alder process is performed at room temperature without any chemical promoter, illustrating the exceptional role of high pressure as a physical promoter.

Over the years, numerous modifications to the structure of proline have been made in order to tune its effects on bioactive compounds. Notably, the introduction of a cyclopropane ring or a fluorine atom has produced interesting results. Herein, we describe the synthesis of a proline containing fluorocyclopropane. This modified amino acid was inserted into a tripeptide, whose conformation was studied by nuclear magnetic resonance and density functional theory calculations., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

The syntheses of the ytterbium(II) distannyl [Yb{Sn(SiMe 3 ) 3 } 2 ·(thf) 4 ] (Yb-Sn) and of its digermyl analogue [Yb{Ge(SiMe 3 ) 3 } 2 ·(thf) 3 ] (Yb-Ge) are presented. The compounds were characterised by multinuclear high-resolution solution NMR spectroscopy, including 171 Yb NMR, and by X-ray diffraction crystallography. The bonding and electronic properties of the two complexes, along with those of the known ytterbium(II) disilyl derivative [Yb{Si(SiMe 3 ) 3 } 2 ·(thf) 3 ] (Yb-Si) and those of the congeneric calcium distannyl [Ca{Sn(SiMe 3 ) 3 } 2 ·(thf) 4 ] (Ca-Sn), were investigated in detail by DFT calculations. This analysis points at a primarily ionic Yb-tetrel bonding, with a small covalent contribution, attributed principally to the 5d(Yb) participation. This weak covalent character is found to be larger for the distannyl Yb-Sn than for its lighter Si- and Ge-derivatives. The covalent component is also found to be greater in Yb-Sn than in Ca-Sn, due to the availability of the 5d(Yb) orbitals for bonding.

The aging of our population is accompanied by an increased prevalence of chronic diseases. Among those, liver, joint and adipose tissue-related pathologies have a major socio-economic impact. They share common origins as they result from a dysregulation of the inflammatory and metabolic status. Plant-derived nutrients and especially polyphenols, exert a large range of beneficial effects in the prevention of chronic diseases but require clinically validated approaches for optimized care management. In this study, we designed an innovative clinical approach considering the metabolites produced by the digestive tract following the ingestion of an artichoke leaf extract. Human serum, enriched with metabolites deriving from the extract, was collected and incubated with human hepatocytes, human primary chondrocytes and adipocytes to determine the biological activity of the extract. Changes in cellular behavior demonstrated that the artichoke leaf extract protects hepatocytes from lipotoxic stress, prevents adipocytes differentiation and hyperplasia, and exerts chondroprotective properties in an inflammatory context. These data validate the beneficial health properties of an artichoke leaf extract at the clinical level and provide both insights and further evidence that plant-derived nutrients and especially polyphenols from artichoke may represent a relevant alternative for nutritional strategies addressing chronic disease issues., Competing Interests: Fabien Wauquier and Line Wittrant-Boutin work for Clinic’n’Cell SAS (Faculty of Medicine and Pharmacy Clermont-Ferrand- France); Asma Boufarai-Aziez, Gwladys Charpentier, Emmanuel Cassin and Guillaume Rousselot work for Evear Extraction and provided the extracts. Laure Guilhaudis, Véronique Roux, Aurélien Viret, Nicolas Macian, Gisèle Pickering, Stéphane Descamps, Hassan Oulyadi and Yohann Wittrant have no conflict of interest to declare.

The versatility of a bulky bis(imino)carbazolate ligand in lead(ii) chemistry is illustrated by the synthesis of a soluble, heteroleptic lead(ii) fluoride and several halide (Cl, Br and I), amide and hydrocarbyl congeners. All complexes have been structurally authenticated, and a full set of 207Pb NMR data is discussed.

The reaction of a silyl dienolate, a Cu(II) salt and TBAT yielding the corresponding copper dienolate is addressed. A combined NMR and cyclic voltammetry analysis first highlight the role of TBAT in the Cu(II) to Cu(I) reduction and the structure of the precatalytic species. From these first results a second set of NMR and theoretical studies enable the determination of the structure and the mechanism of formation of the copper dienolate catalytic species. Finally, we showed that that the copper catalyst promote the E/Z s-cis/s-trans equilibration of the silyl dienolate precursor through a copper dienolate intermediate. All of these results unveil some peculiarities of the catalytic and asymmetric vinylogous Mukaiyama reaction., (© 2021 Wiley-VCH GmbH.)

The first families of alkaline-earth stannylides [Ae(SnPh 3 ) 2 ·(thf) x ] (Ae = Ca, x = 3, 1 ; Sr, x = 3, 2 ; Ba, x = 4, 3 ) and [Ae{Sn(SiMe 3 ) 3 } 2 ·(thf) x ] (Ae = Ca, x = 4, 4 ; Sr, x = 4, 5 ; Ba, x = 4, 6 ), where Ae is a large alkaline earth with direct Ae-Sn bonds, are presented. All complexes have been characterised by high-resolution solution NMR spectroscopy, including 119 Sn NMR, and by X-ray diffraction crystallography. The molecular structures of [Ca(SnPh 3 ) 2 ·(thf) 4 ] ( 1' ), [Sr(SnPh 3 ) 2 ·(thf) 4 ] ( 2' ), [Ba(SnPh 3 ) 2 ·(thf) 5 ] ( 3' ), 4 , 5 and [Ba{Sn(SiMe 3 ) 3 } 2 ·(thf) 5 ] ( 6' ), most of which crystallised as higher thf solvates than their parents 1-6 , were established by XRD analysis; the experimentally determined Sn-Ae-Sn' angles lie in the range 158.10(3)-179.33(4)°. In a given series, the 119 Sn NMR chemical shifts are slightly deshielded upon descending group 2 from Ca to Ba, while the silyl-substituted stannyls are much more shielded than the phenyl ones ( δ 119 Sn/ppm: 1' , -133.4; 2' , -123.6; 3' , -95.5; 4 , -856.8; 5 , -848.2; 6' , -792.7). The bonding and electronic properties of these complexes were also analysed by DFT calculations. The combined spectroscopic, crystallographic and computational analysis of these complexes provide some insight into the main features of these unique families of homoleptic complexes. A comprehensive DFT study (Wiberg bond index, QTAIM and energy decomposition analysis) points at a primarily ionic Ae-Sn bonding, with a small covalent contribution, in these series of complexes; the Sn-Ae-Sn' angle is associated with a flat energy potential surface around its minimum, consistent with the broad range of values determined by experimental and computational methods., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Scalar coupling in organolithium systems can provide access to useful structural and dynamic informations. In this work, we propose a robust method for the accurate measurement of the effective 2 J Li-Li coupling constant in tetramerics alkyllithium aggregates. This crucial information, unavalaible to date, gives a simple access to various structural factors, including the dynamics, solvation and the operative steric hindrance of alkyl chains.

Electronic circular dichroism is one of the most used spectroscopic techniques for peptide and protein structural characterization. However, while valuable experimental spectra exist for α-helix, β-sheet and random coil secondary structures, previous studies showed important discrepancies for β-turns, limiting their use as a reference for structural studies. In this paper, we simulated circular dichroism spectra for the best-characterized β-turns in peptides, namely types I, II, I' and II'. In particular, by combining classical molecular dynamics simulations and state-of-the-art quantum time-dependent density functional theory (with the polarizable embedding multiscale model) computations, two common electronic circular dichroism patterns were found for couples of β-turn types (namely, type I/type II' and type II/type I'), at first for a minimal di-peptide model (Ace-Ala-Ala-NHMe), but also for all sequences tested with non-aromatic residues in the central positions. On the other hand, as expected, aromatic substitution causes important perturbations to the previously found ECD patterns. Finally, by applying suitable approximations, these patterns were subsequently rationalized based on the exciton chirality rule. All these results provide useful predictions and pave the way for a possible experimental characterization of β-turns based on circular dichroism spectroscopy.

3-Nitroindoles are easily reacted with highly substituted γ-allenoates in the presence of a commercially available phosphine catalyst. For instance, allenoates derived from biomolecules such as amino and deoxycholic acids are combined for the first time with 3-nitroindole. The corresponding dearomatized (3+2) tricyclic cycloadducts are obtained as α-regioisomers exclusively. DFT computations shed light on this multi-step reaction mechanism and on the selectivities observed in the sequence., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC 50  = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC 50  > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Biosurfactants such as lipopeptides are amphiphilic compounds produced by microorganisms such as bacteria of the genera of Pseudomonas and Bacillus . Some of these molecules proved to have interesting antimicrobial, antiviral, insecticide, and/or tensioactive properties that are potentially useful for the agricultural, chemical, food, and pharmaceutical industries. Raw milk provides a physicochemical environment that is favorable to the multiplication of a broad spectrum of microorganisms. Among them, psychrotrophic bacterial species, especially members of the genus Pseudomonas , are predominant and colonize milk during cold storage and/or processing. We isolated the strain Pseudomonas sp. UCMA 17988 from raw cow milk, with antagonistic activity against Listeria monocytogenes , Staphylococcus aureus , and Salmonella enterica Newport. Antimicrobial molecules involved in the antagonistic activity of this strain were characterized. A mass spectrometry analysis highlighted the presence of four lipopeptides isoforms. The major isoform (1409 m / z ), composed of 10 carbons in the lipidic chain, was named milkisin C. The three other isoforms detected at 1381, 1395, and 1423 m / z , that are concomitantly produced, were named milkisin A, B, and D, respectively. The structure of milkisin, as confirmed by nuclear magnetic resonance analyses, is closely related to amphisin family. Indeed, the peptidic chain was composed of 11 amino acids, 6 of which are conserved among the family. In conclusion, Pseudomonas sp. UCMA 17988 produces new members of the amphisin family which are responsible for the antagonistic activity of this strain.

The synthesis and identification of unprecedented gem-dianionic phosphorus compounds, that is, gem-dilithium phosphido-boranes Li 2 [RP⋅BH 3 ], with R=Ph or Cy, are reported in THF solution. These were obtained by double deprotonation of the corresponding primary phosphine-borane precursors RPH 2 ⋅BH 3 . Their in-depth structural study, based on multinuclear ( 1 H, 6 Li, 7 Li, 11 B, 13 C, 31 P) mono- and bi-dimensional NMR analyses, indicates a strong influence of the phosphorus substituent on the structure of the gem-dianionic phosphorus structure; a monomeric arrangement was obtained when R=phenyl, whereas a cyclic oligomer was observed for R=cyclohexyl. These compounds represent a new type of useful reagent, and their access paves the way for the concept of "RP synthons" (i.e., RP 2- phosphandiides), likely to be the most flexible precursors of a variety of phosphorus targets., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)