Direct Regio‐, Diastereo‐, and Enantioselective Vinylogous Michael Addition of Prochiral 3‐Alkylideneoxindoles to Nitroolefins

3‐Alkylidene‐2‐oxindoles represent a simple, yet enabling subfamily of indole alkaloids, and their ability to react as electron‐poor acceptors has largely been investigated. In contrast, their utility as pronucleophilic synthons remains elusive. In this context, the present article describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prochiral 3‐alkylideneoxindoles to nitroolefins. A variety of γ‐substituted alkylideneoxindoles carrying two stereocenters at both the γ‐ and δ‐carbon sites was assembled with excellent stereoselectivity and without olefin isomerization or stereochemical ablation.     

Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K(i)=20 nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K(i)=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.     

An Easy Entry to Optically Active Spiroindolinones: Chiral Brønsted Acid‐Catalysed Pictet–Spengler Reactions of Isatins

The first catalytic asymmetric Pictet–Spengler reaction of isatins is presented. BINOL‐derived phosphoric acids were found to be competent catalysts for this transformation, giving challenging spirooxindole structures bearing a quaternary stereocentre with generally good results. The 1,2,3,4‐tetrahydro‐β‐carboline products (spiroindolinones) are the core of some newly discovered anti‐malarial agents.     

Preparation and characterization of Pd-Pb catalysts for selective hydrogenation

The preparation of Pd/-Al₂O₃ and Pd-Pb/-Al₂O₃ catalysts using Pd-acetylacetonate and tetrabutyl-lead (TBPb) has been studied. In the monometallic catalyst the precursor decomposition in air leads to a well dispersed Pd phase. Reacting the Pd/-Al₂O₃ (0.19%) catalyst with TBPb in the presence of adsorbed hydrogen, produces one mol of hydrocarbons (mainly butane) per mol of Pb fixed, suggesting the formation of a surface intermediate; Pd-Pb(C₄H₈)₃. In the absence of hydrogen, the reaction is slower and the evolution of hydrocarbons (mainly butenes) decreases by a factor of 2. As the amount of Pb fixed by both procedures is the same, Pb/Pd₃ = 1.3, other surface compounds must be involved. Characterization by H₂ and CO chemisorption and FTIR spectroscopy of adsorbed CO shows that Pb addition produces a dilution of the surface Pd atoms, preventing the dissociative adsorption of H₂ and inducing the adsorption of CO in the linear form. The XPS spectra of Pd/-Al₂O₃ and Pd-Pb/-Al₂O₃ (0.19 %– 0.27%) indicate a Pb 4f/Pd 3d ratio of 1.4 and a decrease in the Pd 3d/Al 2s intensity ratio with Pb addition. These results suggest that Pb is well dispersed and in close contact with the Pd surface.     

Asymmetric Dimethylarginine Plasma Levels and Endothelial Function in Newly Diagnosed Type 2 Diabetic Patients

It is now well established that major risk factors for cardiovascular diseases (CVD) impact upon endothelial function by decreasing nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA), an endogenous analog of l-arginine, is able to inhibit the activity of endothelial-NO synthase, promoting endothelial dysfunction. Type 2 diabetes (T2D) is characterized by a reduced endothelium-dependent vasodilation and increased ADMA levels and ADMA is strongly associated with micro- and macrovascular diabetic complications. However, there are not a lot of data about the role of ADMA on endothelial function in newly diagnosed T2D patients without cardiovascular (CV) complications. For this aim, we have enrolled forty-five newly diagnosed T2D patients, evaluated by a oral glucose tolerance test, and thirty normal subjects. Endothelium-dependent and -independent vasodilatation was investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh) and sodium nitroprusside. ADMA was measured by high-performance liquid chromatography and insulin resistance (IR) by HOMA. Newly diagnosed T2D patients showed higher ADMA and l-arginine mean values in comparison with normal subjects and a significantly reduced ACh-stimulated forearm blood flow (FBF). In T2D patients FBF was significantly and inversely correlated with ADMA (r = −0.524, p < 0.0001) and in a multivariate regression analysis, ADMA resulted the stronger predictor of FBF, explaining the 27.5% of variability (p < 0.0001). In conclusion, ADMA was strongly related to endothelial dysfunction also in patients with newly diagnosed T2D, without clinically manifest vascular complications. This field is of great interest for understanding the mechanisms underlying the pathogenesis of diabetic disease and its CV complications.     

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure–activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.     

MT1‐Selective Melatonin Receptor Ligands: Synthesis,Pharmacological Evaluation,and Molecular Dynamics Investigation of N‐{[(3‐O‐Substituted)anilino]alkyl}amides

The design of compounds selective for the MT₁ melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT₁ subtype, and only few selective compounds have been reported so far. N‐(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT₁/MT₂ agonists and MT₂‐selective antagonists. We synthesized a new series of N‐(anilinoalkyl)amides bearing 3‐arylalkyloxy or 3‐alkyloxy substituents at the aniline ring, looking for new potent and MT₁‐selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a , which was endowed with high MT₁ binding affinity (pK_i=8.93) and 78‐fold selectivity for the MT₁ receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3‐arylalkyloxy substituent, we built a homology model of the MT₁ receptor based on the β₂ adrenergic receptor crystal structure in its activated state. A binding mode for MT₁ agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT₁ selectivity of compounds with lipophilic arylalkyloxy substituents.     

Effects of protein properties on adsorption and transport in polymer‐grafted ion exchangers: A multiscale modeling study

We use multiscale modeling to study how the molecular properties of a protein affect its adsorption and transport in ion exchange chromatography matrices with either open pores or charged polymers grafted into the pore structure. Coarse‐grained molecular dynamics (MD) simulations of lysozyme, bovine serum albumin, and immunoglobulin show that higher protein net charge leads to greater partitioning into the polymer‐grafted pore space but slower diffusion there due to favorable electrostatic interactions, while larger size decreases both pore space partitioning and diffusion due to steric effects of the polymers. Mass transfer simulations based on the MD results show that the polymer‐grafted systems can enhance the adsorption kinetics if pore space partitioning and diffusion are both sufficiently high. The simulations illustrate that to achieve fast adsorption kinetics, there is a tradeoff between favorable binding and rapid diffusion which largely depends on the charge and size of the protein. © 2017 American Institute of Chemical Engineers AIChE J, 63: 4564–4575, 2017     

水泵水轮机泵工况下近设计点驼峰现象的流动机理研究*

中高比转速水泵水轮机泵工况下近设计点驼峰严重制约了其稳定运行范围,是制约抽水蓄能电站安全与经济运行的关键问题之一。作为流动问题的宏观表现,驼峰现象必然与水泵水轮机内部的非定常流动存在密切关系。为此,基于试验和数值模拟,对水泵水轮机泵工况下可调导叶流道内的非定常流动进行研究,探究模型机泵工况下的压力脉动特性、非定流动机理及与性能曲线稳定性之间的关系。结果表明：在设计和小于设计工况下,可调导叶流道内均存在两种显著的周期性压力脉动。模型机泵工况下的流量扬程曲线在0.45~0.75倍设计流量区间内出现驼峰,频域分析清晰地揭示了以上两种压力脉动是对该驼峰存在重要影响的流动参量。     

Foam injection molding of poly(lactic acid) with environmentally friendly physical blowing agents

Biodegradable polymers present a very narrow processing window, with the suitable processing temperatures close to the degradation conditions. The aim of this work was to analyze the foamability of a biodegradable polymer, namely the poly(lactic acid), PLA. Foam injection molding was conducted by using a blowing agent under high pressure and temperature to produce parts having a cellular core and a compact solid skin (the so-called “structural foam”). The effect of a physical blowing agent (PBA) on density and morphology of foamed parts was characterized. A masterbatch of PLA and talc was prepared and adopted to obtain a compound containing 3% of talc. On adding this percentage of talc to PLA it was possible to obtain foamed parts with a much better morphology.