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https://www.readbyqxmd.com/read/29656543/diastereoselective-synthesis-of-highly-substituted-amino-and-pyrrolidino-tetrahydrofurans-as-lead-like-molecular-scaffolds
#1
Christopher John Moody, Steven Wales, Elena Merisor, Holly Adcock, Christopher Pearce, Ian Strutt, William Lewis, Daniel Hamza
A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2-aryl, 3-carboxy and 4-amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre-functionalised 4-oxofurans, readily prepared from cinnamate esters via oxa-Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C-3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C-4 relative to the other ring substituents...
April 14, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29656465/structural-characterization-of-the-interaction-of-the-fibroblast-growth-factor-receptor-with-a-small-molecule-allosteric-inhibitor
#2
Franziska Kappert, Sridhar Sreeramulu, Hendrik R A Jonker, Christian Richter, Vladimir V Rogov, Ewgenij Proschak, Bruno Hargittay, Krishna Saxena, Harald Schwalbe
The interaction of fibroblast growth factors (FGFs) with their fibroblast growth factor receptors (FGFRs) are important in the signaling network of cell growth and development. SSR128129E (SSR)[1,2], a ligand of small molecular weight with potential anti-cancer properties, acts allosterically on the extracellular domains of FGFRs. Up to now, the structural basis of SSR binding to the D3 domain of FGFR remained elusive. Here, we report the structural characterization of the interaction of SSR with one specific receptor, FGFR3 by NMR spectroscopy...
April 14, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29656443/biological-evaluation-of-selected-3-4-dihydro-2-1h-quinoxalinones-and-3-4-dihydro-1-4-benzoxazin-2-ones-molecular-docking-study
#3
Jelena Petronijević, Nenad Janković, Tatjana P Stanojković, Nenad Joksimović, Nađa Đ Grozdanić, Milan Vraneš, Aleksandar Tot, Zorica Bugarčić
In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4-benzoxazin-2-ones. The results obtained showed that compounds 5, 9-11 have good cytotoxic activity against HeLa cells where the lowest IC50 value (10.46 ± 0.82 μM/mL) was measured for compound 10. Additionally, the most active compounds (5, 9-11) showed much better selectivity for MRC-5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α-glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52...
April 14, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29656194/multiple-dynamic-al-based-floc-layers-on-ultrafiltration-membrane-surfaces-for-humic-acid-and-reservoir-water-fouling-reduction
#4
Baiwen Ma, Wenjiang Li, Ruiping Liu, Gang Liu, Jingqiu Sun, Huijuan Liu, Jiuhui Qu, Walter van der Meer
The integration of adsorbents with ultrafiltration (UF) membranes is a promising method for alleviating membrane fouling and reducing land use. However, adsorbents typically are only injected into the membrane tank once, resulting in a single dynamic protection layer and low removal efficiency over long-term operation. In addition, the granular adsorbents used can cause membrane surface damage. To overcome these disadvantages, we injected inexpensive and loose aluminum (Al)-based flocs directly into a membrane tank with bottom aeration in the presence of humic acid (HA) or raw water taken from the Miyun Reservoir (Beijing, China)...
April 5, 2018: Water Research
https://www.readbyqxmd.com/read/29656141/wnt5a-suppresses-inflammation-driven-intervertebral-disc-degeneration-via-a-tnf-%C3%AE-nf-%C3%AE%C2%BAb-wnt5a-negative-feedback-loop
#5
Zemin Li, Kuibo Zhang, Xiang Li, Hehai Pan, Sibei Li, Fan Chen, Jian Zhang, Zhaomin Zheng, Jianru Wang, Hui Liu
OBJECTIVE: This study was to investigate the molecular role of Wnt5a on inflammation-driven intervertebral disc degeneration (IVDD). METHODS: The expression of Wnt5a was analyzed in human nucleus pulposus (NP) tissues with immunohistochemical staining. The effects of Wnt5a on matrix production were assessed by RT-qPCR and western blotting. Small interfering RNAs (siRNAs), promoter deletion assay, and promoter binding site mutant were used to reveal the molecular role of Wnt5a in TNF-α-induced matrix metalloproteinase (MMP) expression...
April 12, 2018: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/29656109/bile-acids-are-important-direct-and-indirect-regulators-of-the-secretion-of-appetite-and-metabolism-regulating-hormones-from-the-gut-and-pancreas
#6
Rune E Kuhre, Nicolai J Wewer Albrechtsen, Olav Larsen, Sara L Jepsen, Emilie Balk-Møller, Daniel B Andersen, Carolyn F Deacon, Kristina Schoonjans, Frank Reimann, Fiona M Gribble, Reidar Albrechtsen, Bolette Hartmann, Mette M Rosenkilde, Jens J Holst
OBJECTIVE: Bile acids (BAs) facilitate fat absorption and may play a role in glucose and metabolism regulation, stimulating the secretion of gut hormones. The relative importance and mechanisms involved in BA-stimulated secretion of appetite and metabolism regulating hormones from the gut and pancreas is not well described and was the purpose of this study. METHODS: The effects of bile acids on the secretion of gut and pancreatic hormones was studied in rats and compared to the most well described nutritional secretagogue: glucose...
March 17, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29656021/next-generation-neuro-oncology
#7
REVIEW
Michael Weller
Neuro-oncology has evolved as a growing, but still small, highly specialised and multidisciplinary field at the interface of several diagnostic and therapeutic disciplines. The major challenge in the field of primary tumours is to translate the almost unique progress in deciphering the highly complex molecular genetic nature of many primary brain tumours, notably glioblastoma, into advances that allow for clinical benefit for affected patients. Furthermore, metastases to the central nervous system are an increasingly prevalent complication in many systemic cancers...
April 12, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29655854/the-expression-and-distribution-of-a-leptin-receptor-in-the-central-nervous-system-digestive-organs-and-gonads-of-the-giant-freshwater-prawn-macrobrachium-rosenbergii
#8
Jaruwan Poljaroen, Ruchanok Tinikul, Panat Anuracpreeda, Prasert Sobhon, Yotsawan Tinikul
In the present study, the presence and distribution of leptin receptor (LEP-R) in central nervous system, digestive organs, gonads of giant freshwater prawn, Macrobrachium rosenbergii, were investigated with Western blot and immunohistochemistry. By Western blot a LEP-R with a molecular weight (MW) of 100 kDa was detected in the brain, thoracic ganglia, abdominal ganglia, hepatopancreas, all parts of the gastrointestinal tract, ovaries, and testes. In hepatopancreas and foregut, another intense positive band was detected at molecular weight of 30 kDa, which could be an isotype of LEP-R...
April 11, 2018: Acta Histochemica
https://www.readbyqxmd.com/read/29655343/using-reweighting-and-free-energy-surface-interpolation-to-predict-solid-solid-phase-diagrams
#9
Natalie P Schieber, Eric C Dybeck, Michael R Shirts
Many physical properties of small organic molecules are dependent on the current crystal packing, or polymorph, of the material, including bioavailability of pharmaceuticals, optical properties of dyes, and charge transport properties of semiconductors. Predicting the most stable crystalline form at a given temperature and pressure requires determining the crystalline form with the lowest relative Gibbs free energy. Effective computational prediction of the most stable polymorph could save significant time and effort in the design of novel molecular crystalline solids or predict their behavior under new conditions...
April 14, 2018: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29653131/bet-bromodomain-inhibitors-show-anti-papillomavirus-activity-in-vitro-and-block-crpv-wart-growth-in-vivo
#10
Mary A Morse, Karla K Balogh, Sarah A Brendle, Colin A Campbell, Mao X Chen, Rebecca C Furze, Isobel L Harada, Ian D Holyer, Umesh Kumar, Kevin Lee, Rab K Prinjha, Martin Rüdiger, Jon Seal, Simon Taylor, Jason Witherington, Neil D Christensen
The DNA papillomaviruses infect squamous epithelium and can cause persistent, benign and sometimes malignant hyperproliferative lesions. Effective antiviral drugs to treat human papillomavirus (HPV) infection are lacking and here we investigate the anti-papillomavirus activity of novel epigenetic targeting drugs, BET bromodomain inhibitors. Bromodomain and Extra-Terminal domain (BET) proteins are host proteins which regulate gene transcription, they bind acetylated lysine residues in histones and non-histone proteins via bromodomains, functioning as scaffold proteins in the formation of transcriptional complexes at gene regulatory regions...
April 10, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29653071/geomorphology-influencing-the-diversification-of-fish-in-small-order-rivers-of-neighboring-basins
#11
João P Morais-Silva, Alessandra V de Oliveira, Thomaz M C Fabrin, Nathália Alves Diamante, Sônia M A P Prioli, Augusto Frota, Weferson J da Graça, Alberto J Prioli
The current analysis investigates whether the uplift of the Serra da Esperança and the Ponta Grossa Arch in the Serra Geral resulted in ichthyofaunistic changes in adjacent basins. For this, we describe the phylogeographic structure among populations of Trichomycterus collected in hydrographic basins in southern Brazil by using partial nucleotide sequences of the mitochondrial gene Cytochrome C Oxidase subunit I. Analyses revealed that the nomenclature Trichomycterus davisi fails to contain the whole genetic diversity range found in the collected specimens and indicates at least six genetic lineages in Trichomycterus...
March 13, 2018: Zebrafish
https://www.readbyqxmd.com/read/29652606/development-of-pei-rank-sirna-complex-loaded-plga-nanocapsules-for-the-treatment-of-osteoporosis
#12
Deniz Sezlev Bilecen, Hasan Uludag, Vasif Hasirci
Osteoporosis, which is characterized by low bone mineral density and susceptibility to fracture, is caused by increased osteoclastic activity. Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL)/RANK signaling plays an important role in osteoclast differentiation and activation. The current treatment strategies for osteoporosis do not directly address this underlying cause and generates undesired side effects. This led to emergence of controlled delivery systems to increase drug bioavailability and efficacy specifically at the bone tissue...
March 14, 2018: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/29652499/rapid-sampling-of-hydrogen-bond-networks-for-computational-protein-design
#13
Jack B Maguire, Scott E Boyken, David Baker, Brian Kuhlman
Hydrogen bond networks play a critical role in determining the stability and specificity of biomolecular complexes, and the ability to design such networks is important for engineering novel structures, interactions, and enzymes. One key feature of hydrogen bond networks that makes them difficult to rationally engineer is that they are highly cooperative and are not energetically favorable until the hydrogen bonding potential has been satisfied for all buried polar groups in the network. Existing computational methods for protein design are ill-equipped for creating these highly cooperative networks because they rely on energy functions and sampling strategies that are focused on pairwise interactions...
April 13, 2018: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/29652442/antioxidant-hydrolysed-peptides-from-manchurian-walnut-juglansmandshurica-maxim-attenuate-scopolamine-induced-memory-impairment-in-mice
#14
Dayong Ren, Fanrui Zhao, Chunlei Liu, Ji Wang, Yong Guo, Jingsheng Liu, Weihong Min
BACKGROUND: Walnut protein, which is obtained as a by-product of oil expression, has not been used efficiently. Although walnuts are beneficial for cognitive functioning, the potential of their protein composition in strengthening learning and memory functions remains unknown. In this research, the inhibition of memory impairment by the Manchurian walnut hydrolyzed peptide (MWHP) was evaluated. RESULTS: Small-molecular-weight MWHP (<3 kDa) achieved the optimal antioxidative activity...
April 13, 2018: Journal of the Science of Food and Agriculture
https://www.readbyqxmd.com/read/29652127/optical-probes-for-neurobiological-sensing-and-imaging
#15
Eric H Kim, Gregory Chin, Guoxin Rong, Kira E Poskanzer, Heather A Clark
Fluorescent nanosensors and molecular probes are next-generation tools for imaging chemical signaling inside and between cells. Electrophysiology has long been considered the gold standard in elucidating neural dynamics with high temporal resolution and precision, particularly on the single-cell level. However, electrode-based techniques face challenges in illuminating the specific chemicals involved in neural cell activation with adequate spatial information. Measuring chemical dynamics is of fundamental importance to better understand synergistic interactions between neurons as well as interactions between neurons and non-neuronal cells...
April 13, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29651444/an-updated-review-of-the-molecular-mechanisms-in-drug-hypersensitivity
#16
REVIEW
Chun-Bing Chen, Riichiro Abe, Ren-You Pan, Chuang-Wei Wang, Shuen-Iu Hung, Yi-Giien Tsai, Wen-Hung Chung
Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs)...
2018: Journal of Immunology Research
https://www.readbyqxmd.com/read/29651420/the-human-replicative-helicase-the-cmg-complex-as-a-target-for-anti-cancer-therapy
#17
REVIEW
Yeon-Soo Seo, Young-Hoon Kang
DNA helicases unwind or rearrange duplex DNA during replication, recombination and repair. Helicases of many pathogenic organisms such as viruses, bacteria, and protozoa have been studied as potential therapeutic targets to treat infectious diseases, and human DNA helicases as potential targets for anti-cancer therapy. DNA replication machineries perform essential tasks duplicating genome in every cell cycle, and one of the important functions of these machineries are played by DNA helicases. Replicative helicases are usually multi-subunit protein complexes, and the minimal complex active as eukaryotic replicative helicase is composed of 11 subunits, requiring a functional assembly of two subcomplexes and one protein...
2018: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29651407/combination-therapy-with-histone-deacetylase-inhibitors-hdaci-for-the-treatment-of-cancer-achieving-the-full-therapeutic-potential-of-hdaci
#18
REVIEW
Amila Suraweera, Kenneth J O'Byrne, Derek J Richard
Genetic and epigenetic changes in DNA are involved in cancer development and tumor progression. Histone deacetylases (HDACs) are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer. Histone deacetylase inhibitors (HDACi), a novel class of small-molecular therapeutics, are now approved by the Food and Drug Administration as anticancer agents. While they have shown great promise, resistance to HDACi is often observed and furthermore, HDACi have shown limited success in treating solid tumors...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29651360/phosphatase-of-regenerating-liver-3-prl-3-is-overexpressed-in-classical-hodgkin-lymphoma-and-promotes-survival-and-migration
#19
Magnus Aassved Hjort, Håkon Hov, Pegah Abdollahi, Esten Nymoen Vandsemb, Unn-Merete Fagerli, Bendik Lund, Tobias Schmidt Slørdahl, Magne Børset, Torstein Baade Rø
Background: Phosphatase of regenerating liver-3 (PRL-3) is implicated in oncogenesis of hematological and solid cancers. PRL-3 expression increases metastatic potential, invasiveness and is associated with poor prognosis. With this study, we aimed to show a possible oncogenic role of PRL-3 in classical Hodgkin lymphoma (cHL). Methods: PRL-3 expression was measured in 25 cHL patients by immunohistochemistry and gene expression was analyzed from microdissected malignant cells...
2018: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/29650981/optical-characterization-of-surface-adlayers-and-their-compositional-demixing-at-the-nanoscale
#20
Limin Xiang, Michal Wojcik, Samuel J Kenny, Rui Yan, Seonah Moon, Wan Li, Ke Xu
Under ambient conditions, the behavior of a solid surface is often dominated by a molecularly thin adsorbed layer (adlayer) of small molecules. Here we develop an optical approach to unveil the nanoscale structure and composition of small-molecule adlayers on glass surfaces through spectrally resolved super-resolution microscopy. By recording the images and emission spectra of millions of individual solvatochromic molecules that turn fluorescent in the adlayer phase, we obtain ~30 nm spatial resolution and achieve concurrent measurement of local polarity...
April 12, 2018: Nature Communications
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