A comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) of N-phenyl-N'-(2-chloroethyl)urea targeting the colchicine-binding site as anticancer agents

To decipher the mechanism underlying the covalent binding of N-phenyl-N′-(2-chloroethyl)ureas (CEU) to the colchicine-binding site on βII-tubulin and to design new and selective antimitotic drugs, we developed 3D quantitative structure–activity relationships (3D-QSAR) models using CoMFA and CoMSIA analyses. The present study correlates the cell growth inhibition activities of 56 structurally related CEU derivatives to several physicochemical parameters representing steric, electrostatic, and hydrophobic fields. Both CoMFA and CoMSIA models using two different optimum numbers of components (ONC) 10 and 4, respectively, gave good internal predictions and their cross-validated r2 values were between 0.639 and 0.743. These comprehensive CoMFA and CoMSIA models are useful in understanding the structure–activity relationships of CEU. The two models were compared to the X-ray crystal structure of the complex of tubulin–colchicine and analyzed for similarities between the two modes of analysis. These models will inspire the design of new CEU derivatives with enhanced inhibition of tumor cell growth and targeting specificity of βII-tubulin and the cytoskeleton

N-Phenyl-N'-(2-chloroethyl)urea analogues of combretastatin A-4: Is the N-phenyl-N'-(2-chloroethyl)urea pharmacophore mimicking the trimethoxy phenyl moiety ?

A series of novel N-phenyl-N'-(2-chloroethyl)urea derivatives potentially mimicking the structure of combretastatin A-4 were synthesized and tested for their cell growth inhibition and their binding to the colchicine-binding site of beta-tubulin. Compounds 2a, 3a, and 3b were found to inhibit cell growth at the micromolar level on four human tumor cell lines. Flow cytometric analysis indicates that the new compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. Covalent binding of 2a, 3a, and 3b to the colchicine-binding site of beta-tubulin was confirmed also using SDS-PAGE and competition assays

N-Phenyl-N’-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. part 3 : role of carbonyl group

n the course of the development of N-phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents, we investigated the effect of carbonylated substituting chains of the aromatic ring of CEU on their covalent binding to the colchicine-binding site (C-BS). In this study, we found that CEU, 5e, 5f, 8e, and 8f substituted by either a methyl ester or a methyl ketyl group at the ω-position exhibited a significant antiproliferative activity on HT-29, M21, and MCF-7 tumor cells. SDS–PAGE assays and cell cycle analysis confirmed that 5e, 5f, 8e, and 8f covalently bind to the C-BS and arrest the cell division in G2/M phase. Surprisingly, the presence of ω-carboxyl, ω-ethyl esters or ω-amides decreased significantly both the antiproliferative activity and the specificity toward β-tubulin

Comparison of MRI properties between multimeric DOTAGA and DO3A gadolinium-dendron conjugates

The inherent lack of sensitivity of MRI needs the development of new Gd contrast agents in order to extend 20Hz,37%, the application of this technique to cellular imaging. For this purpose, two multimeric MR contrast agents obtained by peptidic coupling between an amido amine dendron and GdDOTAGA chelates (premetalation strategy, G1-4GdDOTAGA) or DO3A derivatives which then were postmetalated (G1-4GdDO-3A) have been prepared. By comparison to the monomers, an increase of longitudinal relaxivity has been observed for both structures. Especially for G1-4GdDO-3A, a marked increase is observed between 20 and 60 MHz. This structure differs from G1-4GdDOTAGA by an increased rigidity due to the aromatic linker between each chelate and the organic framework. This has the effect of limiting local rotational movements, which has a positive impact on relaxivity

Towards a monolithic optical cavity for atom detection and manipulation

We study a Fabry-Perot cavity formed from a ridge waveguide on a AlGaAs substrate. We experimentally determined the propagation losses in the waveguide at 780 nm, the wavelength of Rb atoms. We have also made a numerical and analytical estimate of the losses induced by the presence of the gap which would allow the interaction of cold atoms with the cavity field. We found that the intrinsic finesse of the gapped cavity can be on the order of F ~ 30, which, when one takes into account the losses due to mirror transmission, corresponds to a cooperativity parameter for our system C ~ 1

Direct-to-metal UV-cured hybrid coating for the corrosion protection of aircraft aluminium alloy

Finding eco-efficient and environmentally viable alternatives to chromate coatings represents a fundamental milestone in the aerospace industry. Here, we show a chromate-free approach to protective hybrid coatings on aluminium alloy (AA2024-T3) departing from photoinduced sol–gel and cationic polymerizations. Beginning with a film of n-alkyltrimethoxysilane and diepoxy monomer, we rely on photogenerated superacids to induce the single step formation of two inorganic and organic barrier networks. Such system combines the unique aspects of photopolymerization including fast reactions, temporal control, solvent-free composition and temperature independence. Used without chemical conversion coating or anodizing, some films have passed 2000h of salt spray testing

Distribution spatiale des objets archéologiques et mouvements de matière à l’échelle des versants cultivés : le cas de Mougon (Indre-et-Loire, France)

Cette contribution pose la question de l’utilisation de la géostatistique pour l’interprétation de la répartition des artefacts recueillis en prospection archéologique. L’expérience a été réalisée à partir des données issues des prospections réalisées à Mougon (commune de Crouzilles, Indre-et-Loire, France) dans le cadre d’un projet retenu par l’Action Concertée Incitative « Terrain, Technique, Théorie » du ministère de la recherche. L’objectif initial visait à établir une distinction entre les concentrations d’artefacts susceptibles de signaler la présence de structures archéologiques sous-jacentes et les zones de répartition spatiale aléatoire des artefacts, liée au fumage des terres cultivées et aux processus post-dépositionnels. Après le tri, le comptage et l’enregistrement informatique du mobilier par catégories chronologiques et fonctionnelles, les artefacts collectés en surface ont fait l’objet d’un traitement géostatistique destiné à faciliter la lecture et l’interprétation de leur répartition : la distribution des artefacts a été étudiée au moyen des méthodes géostatistiques de krigeage ordinaire et de la simulation conditionnelle. L’exploitation des données de surface par le biais de la géostatistique a permis, d’une part, de circonscrire précisément l’emplacement des structures archéologiques potentielles et d’autre part, de révéler l’importance des processus post-dépositionnels dans la redistribution des artefacts en surface. Cette expérience est également à l’origine d’une réflexion sur la pertinence des unités de collecte et de représentation du mobilier de prospection.This contribution aims at discussing the use of geostatistics for the interpretation of the spatial surface distribution of archaeological artefacts. The experience was carried out with the artefacts collected in Mougon (Crouzilles, Indre-et-Loire, France) for the ACI TTT project of the French Ministry of Research. The initial purpose of the study was to distinguish the concentrations of artefacts indicating the presence of buried archaeological remains from a random spatial distribution of artefacts due to manuring and post-depositional processes. After all the artefacts were sorted out, counted and recorded, a geostatistical analysis has been performed to interpret the spatial distribution of the surface artefacts : ordinary kriging and conditional simulation were used. The use of geostatistics allowed a precise delimitation of archaeological features. It also revealed the influence of post-depositional processes on the spatial distribution of artefacts. Furthermore, this experiment led us to re-estimate the relevance of the units we used to collect and represent the survey data

Influence of microbial community composition and metabolism on air.sea ΔpCO 2 variation off the western Antarctic Peninsula

We studied CO 2 and O 2 dynamics in the western Antarctic Peninsula (WAP) waters in relation to (1) phytoplankton biomass, (2) microbial community primary production and respiration, and (3), for the first time, phytoplankton composition, during summer and fall in 3 consecutive years (2002, 2003 and 2004). The areal average of ΔpCO 2 (the difference between surface seawater and atmospheric partial pressure of CO 2) for the 3 yr was significantly negative (.20.04 ± 44.3 μatm, p < 0.01) during the summer to fall period in the region, possibly indicating a CO 2 sink. In the southern WAP (i.e. south of Anvers Island), ΔpCO 2 was significantly negative (.43.60 ± 39.06 μatm) during fall. In the northern WAP (north of Anvers Island), ΔpCO 2 values showed a more complex distribution during summer and fall (.4.96 ± 37.6 and 21.71 ± 22.39 μatm, respectively). Chlorophyll a (chl a) concentration averaged 1.03 ± 0.25 μg l.1 and was higher in the south of the peninsula. Phytoplankton composition influenced chl a concentration with higher and lower values for diatom-and phytoflagellate-dominated communities, respectively. A significant negative correlation existed between chl a and ΔpCO 2. From incubation experiments performed in the northern WAP, respiration was low (averaging 5.1 mmol O 2 m.3 d.1), and the net community production (NCP) correlated negatively with ΔpCO 2 and positively with %O 2 saturation. However, despite the high NCP values measured, ΔpCO 2 was significantly positive in the northern WAP during the summer to fall period. Strong mixing and lower chl a concentration may explain this result. In contrast, ΔpCO 2 was significantly negative in the southern WAP, possibly because of high surface water chl a concentration.Facultad de Ciencias Naturales y Muse

Non-invasive assessment of human multifidus muscle stiffness using ultrasound shear wave elastography: A feasibility study

INTRODUCTION: There is a lack of numeric data for the mechanical characterization of spine muscles, especially in vivo data. The multifidus muscle is a major muscle for the stabilization of the spine and may be involved in the pathogenesis of chronic low back pain (LBP). Supersonic shear wave elastography (SWE) has not yet been used on back muscles. The purpose of this prospective study is to assess the feasibility of ultrasound SWE to measure the elastic modulus of lumbar multifidus muscle in a passive stretching posture and at rest with a repeatable and reproducible method. METHOD: A total of 10 asymptotic subjects (aged 25.5±2.2 years) participated, 4 females and 6 males. Three operators performed 6 measurements for each of the 2 postures on the right multifidus muscle at vertebral levels L2-L3 and L4-L5. Repeatability and reproducibility have been assessed according to ISO 5725 standard. RESULTS: Intra-class correlation coefficients (ICC) for intra- and inter observer reliability were rated as both excellent [ICC=0.99 and ICC=0.95, respectively]. Reproducibility was 11% at L2-L3 level and 19% at L4-L5. In the passive stretching posture, shear modulus was significantly higher than at rest (u<0.05). DISCUSSION: This preliminary work enabled to validate the feasibility of measuring the shear modulus of the multifidus muscle with SWE. This kind of measurement could be easily introduces into clinical routine like for the medical follow-up of chronic LBP or scoliosis treatments.The authors are grateful to the ParisTech BiomecAM chair program on subject-specific musculoskeletal modelling for funding (with the support of ParisTech and Yves Cotrel Foundations, Société Générale, Proteor and Covea)

Intramolecular Cyclization of N-phenyl N'(2-chloroethyl)ureas leads to Active N-phenyl-4,5-dihydrooxazol-2-amines Alkylating β-Tubulin Glu198 and Prohibitin Asp40

International audienceThe cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous phenyl '(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEUs subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G/M or G/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, -phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results could be useful for the design of new prodrugs for cancer chemotherapy