Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.

Eukaryotic translation initiation factor 4E (eIF4E) is considered as the corner stone in the cap-dependent translation initiation machinery. Its role is to recruit mRNA to the ribosome through recognition of the 5'-terminal mRNA cap structure (m7GpppN, where G is guanosine, N is any nucleotide). eIF4E is implicated in cell transformation, tumourigenesis, and angiogenesis by facilitating translation of oncogenic mRNAs; it is thus regarded as an attractive anticancer drug target. We have used two approaches to design cap-binding inhibitors of eIF4E by modifying the N7-substituent of m7GMP and replacing the phosphate group with isosteres such as squaramides, sulfonamides, and tetrazoles, as well as by structure-based virtual screening aimed at identifying non-nucleotide cap-binding antagonists. Phosphomimetic nucleotide derivatives and highly ranking virtual hits were evaluated in a series of in vitro and cell-based assays to identify the first non-nucleotide eIF4E cap-binding inhibitor with activities in cell-based assays, N-[(5,6-dihydro-6-oxo-1,3-dioxolo[4,5-g]quinolin-7-yl)methyl]-N'-(2-methyl-propyl)-N-(phenyl-methyl)thiourea (14), including down-regulation of oncogenic proteins and suppression of RNA incorporation into polysomes. Although we did not observe cellular activity with any of our modified m7GMP phosphate isostere compounds, we obtained X-ray crystallography structures of three such compounds in complex with eIF4E, 5'-deoxy-5'-(1,2-dioxo-3-hydroxycyclobut-3-en-4-yl)amino-N7-methyl-guanosine (4a), N7-3-chlorobenzyl-5'-deoxy-5'-(1,2-dioxo-3-hydroxy-cyclobut-3-en-4-yl)amino-guanosine (4f), and N7-benzyl-5'-deoxy-5'-(trifluoromethyl-sulfamoyl)guanosine (7a). Collectively, the data we present on structure-based design of eIF4E cap-binding inhibitors should facilitate the optimisation of such compounds as potential anticancer agents

Simulation moléculaire de fondus de polymères par la méthode de la "Dynamique des particules dissipatives"

Ce travail porte sur la modélisation et la simulation de fondus de Polyéthylène (PE) et de 1,4cis-Polybutadiène (cis-PB) à l échelle mésoscopique par la méthode de la Dynamique des Particules Dissipatives (DPD). Les chaînes polymériques sont représentées par une succession de billes comprenant chacune monomères (variable appelée paramètre de nivellement) et soumises aux forces de la DPD (conservatives,dissipatives et aléatoires). On établit d abord un jeu de paramètres pour les interactions effectives conservatives relatives au PE et au cis-PB pour plusieurs valeurs de d après des simulations de type Monte-Carlo à l échelle microscopique et en utilisant le concept de potentiel de force moyenne. Les lois d échelles du régime de Rouse sont retrouvées pour toutes les longueurs de chaîne. Des résultats en bon accord avec les données expérimentales et les résultats de simulations microscopiques détaillées sont obtenus pour les grandeurs structurales. Une loi d échelle globale reliant la moyenne du carré de la distance bout à bout au nombre d atomes de carbone de la chaîne microscopique sous-jacente est mise en évidence indépendamment de . Par la suite, les paramètres de la force dissipative sont ajustés pour le PE permettant la comparaison des propriétés dynamiques aux échelles micro et méso. On n observe aucune évolution du régime de Rouse vers le régime de reptation, lié aux enchevêtrements et plus réaliste des longueurs de chaînes simulées ici car les potentiels utilisés sont (et se doivent d être) trop faiblement répulsifs. Afin d observer ce changement de régime, on implante enfin un algorithme de non-croisement reproduction artificielle des enchevêtrements.This work deals with the modelisation and the simulation of Polyethylene (PE) and 1,4cis-Polybutadiene (cis-PB) melts at mesoscale using the Dissipative Particle Dynamics (DPD) method. Polymers are represented as chains of beads each one regrouping (called the coarse-graining level) monomers and subjected to the conservative, dissipative, and random DPD forces. First, a set of parameters for the PE and cis-PB effective conservative interactions is established for several from microscopic Monte Carlo simulations and using the mean-force potential concept. Scaling laws of the Rouse regime are recovered for all chain lengths. Results for the structural quantities are in good agreement with experimental data and detailed microscopic simulations. It is even observed a global (independent of the coarse-graining level) scaling law for the evolution of the root mean square end to end distance with the length of the underlying microscopic chain. Then, the parameters of the dissipative force are adjusted for PE, enabling the comparison between dynamical properties at micro and mesoscale. No transition from the Rouse to reptation regime, related to the existence of entanglements, is observed here. This is due to the fact that the potentials used are (and have to be) too weakly repulsive. To overcome this problem, a non-crossing algorithm is implemented to artificially re-introduce entanglements, leading for the moment only, to a slowing down of the dynamics.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Structural and spectroscopic studies of some copper(I) halide tert-butyl isocyanide adducts

Single-crystal structural characterizations confirm the existence of the unusual 1 : 4 copper(I) halide : unidentate ligand adducts [Cu(CNt-Bu)4]X for X = Cl, Br (two forms), I (the chloride and one form of the bromide being solvated) with crystal packing dominated by stacks of interleaving cations. Cu–C range between 1.941(2) and 1.972(4) Å. The structure of the 1 : 2 chloride complex is also recorded, being [ClCu(CNt-Bu)2], with the copper(I) atom environment trigonal planar, while CuCN : (CNt-Bu) (1 : 1) is a single-stranded polymer which spirals about a crystallographic 3-axis (CN scrambled), the ligands being pendant from the …CuCNCuCN… string. The 65Cu static broadline NMR spectra of [Cu(CNt-Bu)4]I and [Cu(CNt-Bu)4]Br·H2O in the solid state exhibit dominant, narrow −1/2 ↔ +1/2 central transition resonances and associated ±1/2 ↔ ±3/2 satellite transition resonances which are characteristic of first-order quadrupole broadened systems, while associated high-resolution 65Cu MAS NMR data provide accurate measurement of the 65Cu isotropic chemical shifts. Both approaches provide complete data on the quadrupole and chemical shift interactions which contribute to these spectra. Far-IR spectra of products of reactions involving a range of CuX : t-BuNC ratios reveal the existence of 1 : 1.5 adducts for X = Br, I. Metal–carbon and metal-halogen bands are assigned in the far-IR spectra, which indicate a binuclear double halogen-bridged structure for the 1 : 1.5 complexes

Quantifying Lake Water Quality Evolution: Coupled Geochemistry, Hydrodynamics, and Aquatic Ecology in an Acidic Pit Lake

Assessment of water quality evolution in the thousands of existing and future mine pit lakes worldwide requires new numerical tools that integrate geochemical, hydrological, and biological processes. A coupled model was used to test alternative hypothesized controls on water quality in a pit lake over ∼8 years. The evolution of pH, Al, and Fe were closely linked; field observations were reproduced with generic solubility equilibrium controls on Fe­(III) and Al and a commonly reported acceleration of the abiotic Fe­(II) oxidation rate by 2–3 orders of magnitude. Simulations indicated an ongoing acidity loading at the site, and the depletion of Al mineral buffering capacity after ∼5 years. Simulations also supported the existence of pH limitation on nitrification, and a limitation on phytoplankton growth other than the commonly postulated P and DIC limitations. Furthermore, the model reproduced the general patterns of salinity, pH, Al, and Fe during an uncontrolled river breach in 2011, however, incorporating sediment biogeochemical feedbacks is required to reproduce the observed postbreach internal alkalinity generation in the lake. The modeling approach is applicable to the study of hydrological, geochemical, and biological interactions for a range of lake and reservoir management challenges

Structural and spectroscopic studies of some copper(I) halide tert-butyl isocyanide adducts

Single-crystal structural characterizations confirm the existence of the unusual 1 : 4 copper(I) halide : unidentate ligand adducts [Cu(CNt-Bu)(4)]X for X = Cl, Br (two forms), I (the chloride and one form of the bromide being solvated) with crystal packing dominated by stacks of interleaving cations. Cu-C range between 1.941(2) and 1.972(4) angstrom. The structure of the 1 : 2 chloride complex is also recorded, being [ClCu(CNt-BU)(2)], with the copper(I) atom environment trigonal planar, while CuCN: (CNt-Bu) (1 : 1) is a single-stranded polymer which spirals about a crystallographic 3-axis (CN scrambled), the ligands being pendant from the ...CuCNCuCN... string. The Cu-65 static broadline NMR spectra of [Cu(CNt-BU)(4)]I and [Cu(CNt-Bu)(4)]Br center dot H2O in the solid state exhibit dominant, narrow -1/2 +1/2 central transition resonances and associated +/- 1/2 +/- 3/2 satellite transition resonances which are characteristic of first-order quadrupole broadened systems, while associated high-resolution Cu-65 MAS NMR data provide accurate measurement of the (CU)-C-65 isotropic chemical shifts. Both approaches provide complete data on the quadrupole and chemical shift interactions which contribute to these spectra. Far-IR spectra of products of reactions involving a range of CuX : t-BuNC ratios reveal the existence of 1 : 1.5 adducts for X = Br, I. Metal-carbon and metal-halogen bands are assigned in the far-IR spectra, which indicate a binuclear double halogen-bridged structure for the 1 : 1.5 complexes