Design of novel camphane-based derivatives with antimycobacterial activity

Although tuberculosis (TB) continues to be one of the leading infectious disease killers globally, it is curable and preventable. Despite the existence of safe, well tolerated and effective drugs used in the TB treatment, the interest in new entities, combinations and regimens increases during the last 10 years. Recently, we reported for a new class of anti-TB agents – camphane-based derivatives with nanomolar activity against Mycobacterium tuberculosis strains. The quantitative structure–activity relationship (QSAR) study on 12 compounds revealed several structural requirements for antimycobacterial activity: two hydrogen bond donors, two or three rings and no large branched substituents. Here, we describe the design of a set of nine novel camphane-based derivatives following these requirements. The compounds were synthesized and tested against M. tuberculosis strain H37Rv. Four of them showed activities in the nanomolar range, significantly higher than the activities in the initial set. The QSAR study based on all 21 derivatives pointed to two main structural requirements for anti-TB activity: two hydrogen bond donors and a side chain with aromatic ring.     

A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.     

Milk feeding level and starter protein content: Effects on growth performance,blood metabolites,and urinary purine derivatives of Holstein dairy calves

The objective of this study was to investigate the effects of milk allowances equal to 526 g/d as moderate (MOD) versus 790 g/d of milk dry matter as high (HI), and starter diets containing 18% or 23% crude protein (CP), on growth performance, blood metabolites, and purine derivative (PD) excretion in the urine of dairy calves. A total of 52 female Holstein dairy calves (40.8 kg of body weight) were randomly assigned to the experimental diets. The treatments were (1) moderate milk and 18% CP starter diet (MOD-18CP); (2) MOD and 23% CP starter diet (MOD-23CP); (3) high milk and 18% CP starter diet (HI-18CP); and (4) HI and 23% CP starter diet (HI-23CP). Calves had free access to a starter feed and water and were weaned on d 53 but remained in the study until d 73. Urine samples were collected during the preweaning period (for 6 consecutive days between d 35 and 40) and postweaning period (for 6 consecutive days between d 65 and 70) to investigate urinary excretion of PD. Starter feed intake, β-hydroxybutyrate (BHB), and blood urea concentrations were reduced; however, average daily gain (ADG) and blood glucose levels increased in calves fed HI before weaning compared with MOD. During the preweaning period, high milk feeding increased total urinary PD excretion but decreased it after weaning. The 23CP diet resulted in higher feed intake and ADG before weaning and higher excretion of allantoin and total excretion of PD compared with the 18CP diet. The HI-23CP treatment resulted in the greatest withers and hip heights at weaning and final measurement, as well as the highest preweaning blood insulin concentrations. In terms of rumen development, MOD-23CP showed the greatest benefits based on starter intake, blood BHB concentration, and urinary excretion of PD. Based on the higher urinary excretion of PD found in HI-fed calves before weaning, it is possible that milk feeding overestimates estimated microbial yield. The results suggest that feeding starters with a higher proportion of CP may help maintain a more balanced ratio of CP to ME during high milk feeding, to avoid protein deficiency due to low starter intake. When calves are fed a high milk allowance, urine excretion of PD may be misinterpreted as a measure of estimated microbial growth and rumen development; this should be considered during calculations of estimated microbial yield in milk-fed calves.     

Palladium(II) extraction from concentrated chloride media: Reactions involving thioamide derivatives

This work focuses on the detailed study of the palladium(II) extraction reactions by N-methyl-N-phenyl-octanthioamide (MPHTA) and N-methyl-N-cyclohexyl-octanthioamide (MCHTA) in toluene, since their ability to efficiently and selectively recover Pd(II) from a wide range of HCl concentrations is already known. Equilibrium data are presented and discussed, and further complemented by information depicted from UV–visible and NMR spectra. The determined apparent molar volumes show that MPHTA is monomeric, and MCHTA exhibits a slight tendency to aggregate. The Pd(II) extraction reactions by MPHTA and MCHTA are equivalent until 4.5 M HCl, passing through the formation of inner-sphere complexes with the metal ion.     

Theoretical investigation of fluorination effect on the charge carrier transport properties of fused anthra-tetrathiophene and its derivatives

The crystal structures of known anthra-tetrathiophene (ATT) and its three fluorinated derivatives (ATT1, ATT2 and ATT3) were predicted by the Monte Carlo-simulated annealing method with the embedded electrostatic potential (ESP) charges. The most stable crystal structures were further optimized by the density functional theory with the dispersion energy (DFT-D) method. In addition, the effect of the electron-withdrawing fluorine atoms on the molecular geometry, molecular stacking, electronic and transport properties of title compounds were investigated by the density functional theory and the incoherent charge-hopping model. The calculated results show that the introduction of fluorine atoms does not affect the molecular planarity but decreases the HOMO-LUMO gap, which is beneficial to electron injection and provides more charge carrier stabilization. The improved electron mobility from ATT to ATT3 is attributed to the favorable molecular packing with strong π–π interaction and the short stacking distance. ATT2 and ATT3 exhibit remarkable angular dependence of mobilities and anisotropic behaviors. The band structures reveal that all the paths with larger transfer integrals are along the directions of large dispersions in the valence band (VB) and conduction band (CB). ATT3 has the largest electron mobility (0.48 cm² V⁻¹ s⁻¹) among the four compounds, indicating that fluorination is an effective approach to improve electron transport.     

传统醇醚的生产工艺技术提升

从产品合成、生产装置、催化剂类型、产品EO分布和游离醇含量以及下游衍生应用等方面介绍了近些年我国传统醇醚工艺技术的升级与进步。     

Framework for sensitivity and uncertainty quantification in the flutter assessment of bridges

The phenomenon of aerodynamic instability caused by wind is usually a major design criterion for long-span cable-supported bridges. If the wind speed exceeds the critical flutter speed of the bridge, this constitutes an Ultimate Limit State. The prediction of the flutter boundary therefore requires accurate and robust models. The state-of-the-art theory concerning determination of the flutter stability limit is presented. Usually bridge decks are bluff and therefore the aeroelastic forces under wind action have to be experimentally evaluated in wind tunnels or numerically computed through Computational Fluid Dynamics (CFD) simulations. The self-excited forces are modelled using aerodynamic derivatives obtained through CFD forced vibration simulations on a section model. The two-degree-of-freedom flutter limit is computed by solving the Eigenvalue problem.A probabilistic flutter analysis utilizing a meta-modelling technique is used to evaluate the effect of parameter uncertainty. A bridge section is numerically modelled in the CFD simulations. Here flutter derivatives are considered as random variables. A methodology for carrying out sensitivity analysis of the flutter phenomenon is developed. The sensitivity with respect to the uncertainty of flutter derivatives and structural parameters is considered by taking into account the probability distribution of the flutter limit. A significant influence on the flutter limit is found by including uncertainties of the flutter derivatives due to different interpretations of scatter in the CFD simulations. The results indicate that the proposed probabilistic flutter analysis provides extended information concerning the accuracy in the prediction of flutter limits.The final aim is to set up a method to estimate the flutter limit with probabilistic input parameters. Such a tool could be useful for bridge engineers at early design stages. This study shows the difficulties in this regard which have to be overcome but also highlights some interesting and promising results.     

Thermodynamics-antioxidant activity relationships of some 4-benzylidenamino-4, 5-dihydro-1h-1,2,4-triazol-5-one derivatives: Theoretical evaluation

Density functional methods were used to predict the antioxidative efficiency of thirteen 4-benzylidenamino-4, 5-dihydro-1H-1,2,4-triazol-5-one derivatives in the gas phase and in the solution phase (water and benzene). Optimized geometries of molecules and reaction thermodynamic energies (enthalpies and reaction-free energies) of three main antioxidant mechanisms (hydrogen atom transfer, single electron transfer-proton transfer, and sequential proton loss electron transfer) were studied at B3LYP/6-31G (d,p) level. Solvent contributions to thermodynamic energies were computed employing integral equation formalism integral equation formalism polarized continuum model method. Obtained results revealed that the three main working mechanisms were endothermic, but not spontaneous especially in the gas phase. We found that the single electron transfer process from the anionic form was more preferable than that from the neutral form in the gas phase. The comparison of the ionization potentials of 4-benzylidenamino-4, 5-dihydro-1H-1,2,4-triazol-5-one derivatives to those of classical antioxidants (gallic acid, caffeic acid, ferulic acid, and ascorbic acid) indicated that the electron transfer mechanism was more predominant in the thirteen 4-benzylidenamino-4, 5-dihydro-1H-1,2,4-triazol-5-one derivative compounds. Thermodynamically, single electron transfer process from the anionic form was the most preferable mechanism in the gas phase. Solvent effect drastically modified thermodynamic energies of mechanisms. The proton transfer process was the thermodynamically favored mechanism as compared to other mechanisms in both solvents. It is worth mentioning that all the mechanisms were found not to be spontaneous in the solution phase except the proton transfer process.     

Well‐Defined Functional Linear Aliphatic Diblock Copolyethers: A Versatile Linear Aliphatic Polyether Platform for Selective Functionalizations and Various Nanostructures

Low‐temperature anionic ring‐opening homopolymerizations and copolymerizations of two glycidol derivatives (allyl glycidyl ether (AGE) and ethoxyethyl glycidyl ether (EEGE)) are studied using a metal‐free catalyst system, 3‐phenyl‐1‐propanol (PPA) (an initiator) and 1‐tert‐butyl‐4,4,4‐tris(dimethylamino)‐2,2‐bis[tris‐(dimethylamino)phosphoranylidenamino]‐2Λ⁵,4Λ⁵‐catenadi(phosphazene) (t‐Bu‐P₄) (a promoter) in order to obtain well‐defined functional linear polyethers and diblock copolymers. With the aid of the catalyst system, AGE is found to successfully undergo anionic ring‐opening polymerization (ROP) even at room temperature (low reaction temperature) without any side reactions, producing well‐defined linear AGE‐homopolymer in a unimodal narrow molecular weight distribution. Under the same conditions, EEGE also undergoes polymerization, producing a linear EEGE‐homopolymer in a unimodal narrow molecular‐weight distribution. In this case, however, a side reaction (i.e., chain‐transfer reaction) is found to occur at low levels during the early stages of polymerization. The chemical properties of the monomers in the context of the homopolymerization reactions are considered in the design of a protocol used to synthesize well‐defined linear diblock copolyethers with a variety of compositions. The approach, anionic polymerization via the sequential step feed of AGE and EEGE as the first and second monomers, is found to be free from side reactions at room temperature. Each block of the obtained linear diblock copolymers undergoes selective deprotection to permit further chemical modification for selective functionalization. In addition, thermal properties and structures of the polymers and their post‐modification products are examined. Overall, this study demonstrates that a low‐temperature metal‐free anionic ROP using the PPA/t‐Bu‐P₄ catalyst system is suitable for the production of well‐defined linear AGE‐homopolymers and their diblock copolymers with the EEGE monomer, which are versatile and selectively functionalizable linear aliphatic polyether platforms for a variety of post‐modifications, nanostructures, and their applications.     

Design and synthesis of soluble dibenzosuberane-substituted fullerene derivatives for bulk-heterojunction polymer solar cells

Two new dibenzosuberane-substituted fullerene derivatives, dibenzosuberane-C₆₀ mono-adduct (DBSCMA) and bis-adduct (DBSCBA) were synthesized using a classical cyclopropanation reaction via a tosylhydrazone route for application as acceptor materials in polymer solar cells (PSCs). DBSCBA shows good solubility in common organic solvents and both derivatives were characterized by ¹HNMR, ¹³C NMR, MALD-TOF, elemental analysis and UV–vis absorption measurements. The shift of fullerene energy levels induced by the dibenzosuberane substitution was investigated by using theoretical simulations and ultraviolet photoelectron spectroscopy. Bulk-heterojunction PSCs based on poly (3-hexylthiophene) (P3HT) and dibenzosuberane-C₆₀ derivatives were fabricated and optimized by adjusting the donor/acceptor ratio and using thermal annealing and solvent additive. The morphologies of the active layers processed under different conditions were also examined by atomic force microscopy. When tested under an illumination of AM 1.5 G at 100 mW/cm², the highest power conversion efficiency of the devices using DBSCBA is 3.70% which is superior to that of conventional P3HT:PCBM devices.