Directed Positioning of Organometallic Fragments Inside a Calix[4]arene Cavity

A hemispherical diphosphane based on a calixarene allows encapsulation of reactive M–R fragments (M=transition metal; R=H, alkyl, CO) inside the calixarene cavity. The ruthenium complex 1 has an unprecedented sandwich structure that contains a CO ligand confined between two phosphane-substituted phenyl rings. The separation between the CO segment and the two aromatic rings is only 2.75 Å!     

Preliminary Study of New Gallium-68 Radiolabeled Peptide Targeting NRP-1 to Detect Brain Metastases by Positron Emission Tomography

Due to their very poor prognosis and a fatal outcome, secondary brain tumors are one of the biggest challenges in oncology today. From the point of view of the early diagnosis of these brain micro- and macro-tumors, the sensitivity and specificity of the diagnostic tools constitute an obstacle. Molecular imaging, such as Positron Emission Tomography (PET), is a promising technique but remains limited in the search for cerebral localizations, given the commercially available radiotracers. Indeed, the [¹⁸F]FDG PET remains constrained by the physiological fixation of the cerebral cortex, which hinders the visualization of cerebral metastases. Tumor angiogenesis is recognized as a crucial phenomenon in the progression of malignant tumors and is correlated with overexpression of the neuropilin-1 (NRP-1) receptor. Here, we describe the synthesis and the photophysical properties of the new gallium-68 radiolabeled peptide to target NRP-1. The KDKPPR peptide was coupled with gallium-68 anchored into a bifunctional NODAGA chelating agent, as well as Cy5 for fluorescence detection. The Cy5 absorbance spectra did not change, whereas the molar extinction coefficient (ε) decreased drastically. An enhancement of the fluorescence quantum yield (φ_F) could be observed due to the better water solubility of Cy5. [⁶⁸Ga]Ga-NODAGA-K(Cy5)DKPPR was radiosynthesized efficiently, presented hydrophilic properties (log D = −1.86), and had high in vitro stability (>120 min). The molecular affinity and the cytotoxicity of this new chelated radiotracer were evaluated in vitro on endothelial cells (HUVEC) and MDA-MB-231 cancer cells (hormone-independent and triple-negative line) and in vivo on a brain model of metastasis in a nude rat using the MDA-MB-231 cell line. No in vitro toxicity has been observed. The in vivo preliminary experiments showed promising results, with a high contrast between the healthy brain and metastatic foci for [⁶⁸Ga]Ga-NODAGA-K(Cy5)DKPPR.     

Side chain liquid crystalline polymers: Electric field effects and nonlinear properties

Side chain liquid crystalline polymers offer unique advantages as a new class of organic materials with potential for nonlinear optical response. Synthesis of a number of cyanobiphenyl-based side chain polymers was carried out employing the concept of having the cyanobiphenyl species serve concomitantly as both the linear optical chromophore and the mesogenic moiety in the polymer. The thermal behavior of these polymers was studied by DSC, optical microscopy and X-ray diffraction. Thin polymeric films were spin coated and electric field poling measurements were carried out as a function of temperature. The second harmonic (SH) coefficients d₃₃ and d₃₁ were measured by Maker fringe analysis and compared with the values predicted by molecular statistical models. The results showed that one can gain in net polar ordering by starting with a liquid crystalline system. The enhancement in d₃₃ when < P<₂ > = 0,6 was found to be a factor of 2,3-3,3 over the isotropic case ( P<₂ > = 0). The relaxation process was investigated. Both the presence of liquid crystal character in the material and the temperature at which the films were stored below Tg appeared important in determining the thermal stability of the SH coefficients.     

Ab initio study of organic mixed valency

A series of six radical cations of the type (D L D)⁺ was investigated at the ab initio unrestricted Hartree–Fock level. One localized and one delocalized conformation were systematically searched by full geometry optimization. At both nuclear arrangements, mostly found as being minima in the symmetry‐restrained Hartree–Fock framework, excitation energies were calculated through the expansion of the wave function on single electronic excitations of the Hartree–Fock fundamental determinant and at the unrestricted Hartree–Fock or at the multiconfigurational self consistent field levels. Few calculations were also performed by taking into account some part of the electronic correlation. Except for N,N,N′,N′‐tetramethyl p‐phenylenediamine, all the studied compounds are localized stable cations, at the symmetry‐restrained Hartree–Fock level. However, the reoptimization of their wave function changes this observation since only three of them seem to conserve a localized stable conformation. Most of the studied systems are characterized by one or two excited electronic states very close to the fundamental one and should thus present an unresolved broadened first absorption band in the near‐infrared region. These features are in agreement with the available experimental data. Strong Hartree–Fock instabilities are found for the delocalized structure and put in relation with the existence of the large nonadiabatic coupling in this conformational region. The solvent influence is discussed in the Onsager dipolar reaction field framework. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 76: 552–573, 2000     

Identification of Polyphenol Derivatives as Novel SARS-CoV-2 and DENV Non-Nucleoside RdRp Inhibitors

The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47/DF-51 and SARS-CoV-2/DENV RdRp, respectively, including chelating with Mg²⁺ near polymerase active site. This work discovered the inhibitory effect of two polyphenols on distinct viral RdRp, which are expected to be developed into broad-spectrum, non-nucleoside RdRp inhibitors with new scaffold.     

An object-oriented hybrid symbolic/numerical approach for the development of finite element codes

The association of object-oriented programming and symbolic computation techniques introduces certain changes in finite element code organization. The purpose of this approach is to speed up the design of new formulations. Previous papers have described the basic concepts of the method. In this paper, the focus is placed on functional aspects of symbolic tools for the development of finite element formulations. Two practical examples are used to illustrate this point. The first is a space-time formulation for an incompressible flow driven by the Navier–Stokes equations, and the second is a finite element derivation of the total potential energy for linear elasticity.     

Cytotoxic and Antioxidant Activities of Imine Analogs of Trans-Resveratrol towards Murine Neuronal N2a Cells

Trans-resveratrol is a natural polyphenol showing numerous biological properties, especially anti-tumoral and antioxidant activity. Among numerous resveratrol derivatives, aza-stilbenes, which bear an imine bound, show interesting biological activities. In the present study, we synthesized a series of imine analogs of trans-resveratrol (seven aza-stilbenes) following an easy and low-cost procedure of green chemistry. The toxicity of synthesized aza-stilbenes, which is currently unknown, was evaluated on murine neuronal N2a cells, comparatively to trans-resveratrol, by considering: cell density evaluated by staining with sulforhodamine 101; esterase activity, which is a criteria of cell viability, by staining with fluorescein diacetate; and transmembrane mitochondrial potential, which is known to decrease during cell death, by staining with DiOC₆(3) using flow cytometry. In addition, the antioxidant activity was quantified with the KRL (Kit Radicaux Libres) assay, the DPPH (2,2′-diphenyl-1-picrylhydrazyl radical) assay and the FRAP (ferric reducing antioxidant power) assay. The PAOT (Pouvoir Antioxidant Total) score was also used. The aza-stilbenes provide different cytotoxic and antioxidant activities, which are either higher or lower than those of trans-resveratrol. Based on their cytotoxic and antioxidant characteristics, all synthesized aza-stilbenes are distinguished from trans-resveratrol.     

Estimating the Analytical Performance of Raman Spectroscopy for Quantification of Active Ingredients in Human Stratum Corneum

Confocal Raman microscopy (CRM) has become a versatile technique that can be applied routinely to monitor skin penetration of active molecules. In the present study, CRM coupled to multivariate analysis (namely PLSR—partial least squares regression) is used for the quantitative measurement of an active ingredient (AI) applied to isolated (ex vivo) human stratum corneum (SC), using systematically varied doses of resorcinol, as model compound, and the performance is quantified according to key figures of merit defined by regulatory bodies (ICH, FDA, and EMA). A methodology is thus demonstrated to establish the limit of detection (LOD), precision, accuracy, sensitivity (SEN), and selectivity (SEL) of the technique, and the performance according to these key figures of merit is compared to that of similar established methodologies, based on studies available in literature. First, principal components analysis (PCA) was used to examine the variability within the spectral data set collected. Second, ratios calculated from the area under the curve (AUC) of characteristic resorcinol and proteins/lipids bands (1400–1500 cm⁻¹) were used to perform linear regression analysis of the Raman spectra. Third, cross-validated PLSR analysis was applied to perform quantitative analysis in the fingerprint region. The AUC results show clearly that the intensities of Raman features in the spectra collected are linearly correlated to resorcinol concentrations in the SC (R² = 0.999) despite a heterogeneity in the distribution of the active molecule in the samples. The Root Mean Square Error of Cross-Validation (RMSECV) (0.017 mg resorcinol/mg SC), The Root Mean Square of Prediction (RMSEP) (0.015 mg resorcinol/mg SC), and R² (0.971) demonstrate the reliability of the linear regression constructed, enabling accurate quantification of resorcinol. Furthermore, the results have enabled the determination, for the first time, of numerical criteria to estimate analytical performances of CRM, including LOD, precision using bias corrected mean square error prediction (BCMSEP), sensitivity, and selectivity, for quantification of the performance of the analytical technique. This is one step further towards demonstrating that Raman spectroscopy complies with international guidelines and to establishing the technique as a reference and approved tool for permeation studies.     

Gas Flow Measurements by 3D Particle Tracking Velocimetry Using Coloured Tracer Particles

This work describes an original approach for 3D Particle Tracking Velocimetry (3D PTV), applicable also for gaseous flows and based on tracer particles of different colours. On the images acquired by several cameras, tracer particles are handled by colour recognition and 3D localisation. Then, the PTV tracking algorithm rebuilds the trajectories of the tracer particles using a criterion of Minimum Acceleration. Theoretical and numerical calculations are first presented to demonstrate that the employed coloured tracer particles follow in a suitable manner the considered gas flows. The test cases analysed comprise low Reynolds number flows involving a variety of interesting features, in particular boundary layer separation, continuous acceleration and recirculations. The experimental setup and the 3D PTV procedure are then described. All results are analysed in a quantitative manner and demonstrate the performance of the developed measurement strategy in gas flows.