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.     

Characterization of Extra Virgin Olive Oil from Southern Brazil

Six olive oils extracted from the cultivars Arbequina, Arbosana, Coratina, Frantoio, Koroneiki, and Picual from 2017 and 2018 harvests, cultivated in Pinheiro Machado, Rio Grande do Sul, Brazil, are evaluated for standard oil composition parameters and bioactive constituents (pigments, tocopherols, and phenolic compounds). Multivariate principal component analysis (PCA) and univariate ANOVA and Fisher's LSD test are used to verify the effect of cultivar and harvest year on oil composition. Olive oil composition met extra virgin olive oil (EVOO) standard parameters and is influenced by both cultivar and harvest year. EVOO produced in 2018 has greater chlorophyll, caffeic acid, ligstroside aglycone, hydroxyoleuropein aglycone, syringic acid, and hydroxytyrosol acetate contents than the EVOOs from 2017. Linoleic acid, ferulic acid, ligstroside aglycone, and hydroxytyrosol acetate are the variables whose contents most contributed to the differentiation of oils by cultivar in both harvest years. Chemical characterization analyses allow for the differentiation of oil composition based on harvest year and cultivar. Metabolic quality data obtained here support the establishment of a local EVOO profile and the compounds that most contributed to treatment differentiation may serve as markers that can be utilized in determining origin, cultivar, and harvest year. Practical Applications: Olive production in Brazil is recent and is based on European cultivars which have not been bred for the local environmental conditions. Therefore, the measurement of olive oil metabolic quality will determine cultivar adaptability to local edaphoclimatic conditions as well as assist in the establishment of a standard of identity for the product and promote the development of its market. Olive oil produced in Southern Brazil shows high quality, and is especially rich in phenolic compounds. Although harvest year influences oil composition, oil from both harvests meet EVOO standards and cultivar specific metabolic markers are observed. This study provides the foundation for olive producers in Southern Brazil to seek authentication of the geographical origin of olive oil.     

Variation of poly(vinylidene fluoride) morphology due to radial cold flow in a flexible pipe

A subsea flexible pipe containing isotropic poly(vinylidene fluoride) (PVDF) layers is subjected to rapid decompression after being put in pressurized equilibrium with a fluid containing supercritical CO₂. The PVDF layers have flowed radially into gaps of adjacent metallic coils forming whitened noses. Microbeam small‐angle X‐ray scattering (SAXS) scanning reveals a considerable morphological gradient in the polymer layers. PVDF layers (inner: wear, outer: barrier) in two zones (undamaged and damaged) are scanned. Far from noses and damage zone, the samples are isotropic without voids. Their morphological parameters are determined and compared to virgin material. Approaching the noses, the structure turns into highly oriented microfibrils perpendicular to the local flow into the gaps. Here, voids extend parallel to the microfibrils. At edges of the metallic structure, they turn more perpendicular to the layer. Crystallite orientation extends out to both sides of the whitened nose regions, but in the undamaged samples, tilting of the orientation direction and void‐formation are restricted to the white regions: successive mechanisms of cold drawing are mapped into space. Under the damaged spot, voids and crystallite orientation extend through the entire layer. POLYM. ENG. SCI., 55:2869–2877, 2015. © 2015 Society of Plastics Engineers     

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs

Boronic acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two-step synthesis that relies on the solid and versatile copper-catalyzed azide–alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC-2, with K_i values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring bla_KPC-2. In particular, compound 1 e , bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (K_i=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (K_i=20 nM, MIC in KPC-Kpn 0.5 μg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.     

Platinum(II) Complexes Bearing Triphenylphosphine and Chelating Oximes: Antiproliferative Effect and Biological Profile in Resistant Cells

Platinum(II) complexes of the type [Pt(Cl)(PPh₃){(κ²-N,O)-(1{C(R)=N(OH)-2(O)C₆H₄})}] with R=Me, H, ( 1 and 2 ) were synthesized and characterized. Single-crystal X-ray diffraction confirmed the proposed (SP4-3) configuration for 1 . Study of the antiproliferative activity, performed on a panel of human tumor cell lines and on mesothelial cells, highlighted complex 2 as the more effective. In particular, it showed a remarkable cytotoxicity in ovarian carcinoma cells (A2780) and interestingly, a significant antiproliferative effect on cisplatin resistant cells (A2780cis). Investigation into the intracellular mechanism of action demonstrated that 2 had a lower ability to platinate DNA than did cisplatin, which was taken as reference, and a notably higher uptake in resistant cells. A significant accumulation in mitochondria, along with the ability to induce concentration-dependent mitochondrial membrane depolarization and intracellular reactive oxygen species production, allowed us to propose a mitochondrion-mediated pathway as responsible for the interesting cytotoxic profile of complex 2 .     

5-Ethynyluridine: A Bio-orthogonal Uridine Variant for mRNA-Based Therapies and Vaccines

The identification of pseudo- and N¹-methylpseudo-uridine (Ψ and mΨ, respectively) as immunosilent uridine analogues has propelled the development of mRNA-based vaccines and therapeutics. Here, we have characterised another uridine analogue, 5-ethynyluridine (EU), which has an ethynyl moiety. We show that this uridine analogue does not cause immune activation in human macrophages, as it does not induce interleukin-6 secretion or expression of the inflammatory and antiviral genes MX1, PKR, and TAP2. Moreover, EU allows for prolonged expression, as shown with mRNA coding for yellow fluorescent protein (YFP). Side-by-side comparisons of EU with unmodified, Ψ, and mΨ revealed that EU-modified mRNA is expressed at lower levels, but confers similar stability and low immunogenicity to the other uridine analogues. Furthermore, structure analysis of modified mRNAs suggests that the observed phenotype is largely independent of RNA folding. Thus, EU is a potential candidate for RNA-based vaccines and therapeutics.     

Performance of limestone-based sorbent for sorption-enhanced gasification in dual interconnected fluidized bed reactors

A possibility to carry out sorption-enhanced gasification (SEG) is represented by its integration with the calcium looping concept in dual interconnected fluidized beds (DIFB). This article is focused on the sorbent CO₂ uptake performance and attrition/fragmentation tendency when operating conditions simulating those of a DIFB-SEG process are adopted. Experiments were carried out on a commercial Italian limestone in a laboratory-scale DIFB reactor. Carbonation was carried out in a range of test conditions, including variable temperature (600–700°C) and absence/presence of steam (10% by volume); CO₂ concentration was set at 10% by volume. The characterization is extended by investigating the behavior of preprocessed DIFB-SEG samples on impact fragmentation tests, conducted in an ex situ apparatus. Tests were carried out for impact velocities in the range 17–45 m/s. Results were discussed considering both the impact velocity value and the operating conditions under which the sample was preprocessed in the fluidized bed.     

Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice

It has recently been shown that tocotrienols are the components of vitamin E responsible for inhibiting the growth of human breast cancer cells in vitro, through an estrogen-independent mechanism. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. To investigate the molecular basis of the effect of tocotrienols, we injected MCF-7 breast cancer cells into athymic nude mice. Mice were fed orally with 1 mg/d of tocotrienol-rich fraction (TRF) for 20 wk. At end of the 20 wk, there was a significant delay in the onset, incidence, and size of the tumors in nude mice supplemented with TRF compared with the controls. At autopsy, the tumor tissue was excised and analyzed for gene expression by means of a cDNA array technique. Thirty out of 1176 genes were significantly affected. Ten genes were down-regulated and 20 genes up-regulated with respect to untreated animals, and some genes in particular were involved in regulating the immune system and its function. The expression of the interferon-inducible transmembrane protein-1 gene was significantly up-regulated in tumors excised from TRF-treated animals compared with control mice. Within the group of genes related to the immune system, we also found that the CD59 glycoprotein precursor gene was up-regulated. Among the functional class of intracellular transducers/effectors/modulators, the c-myc gene was significantly down-regulated in tumors by TRF treatment. Our observations indicate that TRF supplementation significantly and specifically affects MCF-7 cell response after tumor formation in vivo and therefore the host immune function. The observed effect on gene expression is possibly exerted independently from the antioxidant activity typical of this family of molecules.     

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains

Chloroquine is commonly used in the treatment and prevention of malaria, but Plasmodium falciparum, the main species responsible for malaria‐related deaths, has developed resistance against this drug. Twenty‐seven novel chloroquine (CQ) analogues characterized by a side chain terminated with a bulky basic head group, i.e., octahydro‐2H‐quinolizine and 1,2,3,4,5,6‐hexahydro‐1,5‐methano‐8H‐pyrido[1,2‐a][1,5]diazocin‐8‐one, were synthesized and tested for activity against D‐10 (CQ‐susceptible) and W‐2 (CQ‐resistant) strains of P. falciparum. Most compounds were found to be active against both strains with nanomolar or sub‐micromolar IC₅₀ values. Eleven compounds were found to be 2.7‐ to 13.4‐fold more potent than CQ against the W‐2 strain; among them, four cytisine derivatives appear to be of particular interest, as they combine high potency with low cytotoxicity against two human cell lines (HMEC‐1 and HepG2) along with easier synthetic accessibility. Replacement of the 4‐NH group with a sulfur bridge maintained antiplasmodial activity at a lower level, but produced an improvement in the resistance factor. These compounds warrant further investigation as potential drugs for use in the fight against malaria.