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https://www.readbyqxmd.com/read/28092952/total-synthesis-of-zaragozic-acid-c-implementation-of-photochemi-cal-c-sp3-h-acylation
#1
Takahiro Kawamata, Masanori Nagatomo, Masayuki Inoue
Zaragozic acid C (1) was isolated as a potent squalene synthase inhibitor. The 2,8-dioxabicyclo[3.2.1]octane core of 1 is decorated with the three hydroxycarbonyl (C3,4,5), two hydroxy (C4,7), one acyloxy (C6), and one alkyl (C1) groups. Installation of the contiguous C4- and C5-fully-substituted carbons presents a formidable synthetic challenge. Our approach to addressing this problem utilized a two-step photochemical C(sp3)-H acylation. Persilylated D-gluconolactone 4 was derivatized into 3 with the 1,2-diketone moiety at the C5-tetrasubstituted center...
January 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28077967/integrated-omics-analyses-reveal-the-details-of-metabolic-adaptation-of-clostridium-thermocellum-to-lignocellulose-derived-growth-inhibitors-released-during-the-deconstruction-of-switchgrass
#2
Suresh Poudel, Richard J Giannone, Miguel Rodriguez, Babu Raman, Madhavi Z Martin, Nancy L Engle, Jonathan R Mielenz, Intawat Nookaew, Steven D Brown, Timothy J Tschaplinski, David Ussery, Robert L Hettich
BACKGROUND: Clostridium thermocellum is capable of solubilizing and converting lignocellulosic biomass into ethanol. Although much of the work-to-date has centered on characterizing this microbe's growth on model cellulosic substrates, such as cellobiose, Avicel, or filter paper, it is vitally important to understand its metabolism on more complex, lignocellulosic substrates to identify relevant industrial bottlenecks that could undermine efficient biofuel production. To this end, we have examined a time course progression of C...
2017: Biotechnology for Biofuels
https://www.readbyqxmd.com/read/28058212/complement-related-kidney-diseases-recurrence-after-transplantation
#3
REVIEW
Maurizio Salvadori, Elisabetta Bertoni
The recurrence of renal disease after renal transplantation is becoming one of the main causes of graft loss after kidney transplantation. This principally concerns some of the original diseases as the atypical hemolytic uremic syndrome (HUS), the membranoproliferative glomerulonephritis (MPGN), in particular the MPGN now called C3 glomerulopathy. Both this groups of renal diseases are characterized by congenital (genetic) or acquired (auto-antibodies) modifications of the alternative pathway of complement...
December 24, 2016: World Journal of Transplantation
https://www.readbyqxmd.com/read/28028023/incomplete-inhibition-by-eculizumab-mechanistic-evidence-for-residual-c5-activity-during-strong-complement-activation
#4
Markus J Harder, Nadine Kuhn, Hubert Schrezenmeier, Britta Höchsmann, Inge von Zabern, Christof Weinstock, Thomas Simmet, Daniel Ricklin, John D Lambris, Arne Skerra, Markus Anliker, Christoph Q Schmidt
Eculizumab inhibits the terminal, lytic pathway of complement by blocking the activation of the complement protein C5 and shows remarkable clinical benefits in certain complement-mediated diseases. However, several reports suggest that activation of C5 is not always completely suppressed in patients even under excess of eculizumab over C5 indicating that residual C5 activity may derogate the drug's therapeutic benefit under certain conditions. By using eculizumab and the tick-derived C5 inhibitor coversin we determine conditions ex vivo in which C5-inhibition is incomplete...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/27988521/inhibitors-of-acetylcholinesterase-derived-from-7-methoxytacrine-and-their-effects-on-the-choline-transporter-cht1
#5
Zdenka Kristofikova, Jan Ricny, Ondrej Soukup, Jan Korabecny, Eugenie Nepovimova, Kamil Kuca, Daniela Ripova
BACKGROUND: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. METHODS: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. RESULTS: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA...
December 17, 2016: Dementia and Geriatric Cognitive Disorders
https://www.readbyqxmd.com/read/27977428/breaking-down-the-complement-system-a-review-and-update-on-novel-therapies
#6
Yuvaram N V Reddy, Andrew M Siedlecki, Jean M Francis
PURPOSE OF REVIEW: The complement system represents one of the more primitive forms of innate immunity. It has increasingly been found to contribute to pathologies in the native and transplanted kidney. We provide a concise review of the physiology of the complement cascade, and discuss current and upcoming complement-based therapies. RECENT FINDINGS: Current agents in clinical use either bind to complement components directly or prevent complement from binding to antibodies affixed to the endothelial surface...
December 12, 2016: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27939824/pulmonary-platelet-accumulation-induced-by-catecholamines-its-involvement-in-lipopolysaccharide-induced-anaphylaxis-like-shock
#7
Zhiqian Yu, Hiroko Saito, Hirotada Otsuka, Yosuke Shikama, Hiromi Funayama, Mai Sakai, Shigeo Murai, Masanori Nakamura, Takashi Yokochi, Haruhiko Takada, Shunji Sugawara, Yasuo Endo
Intravenously injected lipopolysaccharides (LPS) rapidly induce pulmonary platelet accumulation (PPA) and anaphylaxis-like shock (ALS) in mice. Macrophages reportedly release catecholamines rapidly upon stimulation with LPS. Here, we examined the involvement of macrophage-derived catecholamines in LPS-induced PPA and ALS. A catecholamine or Klebsiella O3 (KO3) LPS was intravenously injected into mice, with 5-hydroxytryptamine in the lung being measured as a platelet marker. The tested catecholamines induced PPA, leading to shock...
February 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/27932157/belatacept-and-eculizumab-for-treatment-of-calcineurin-inhibitor-induced-thrombotic-microangiopathy-after-kidney-transplantation-case-report
#8
J Merola, P S Yoo, J Schaub, J D Smith, M I Rodriguez-Davalos, E Tichy, D C Mulligan, W Asch, R Formica, M Kashgarian, S Kulkarni
Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome...
November 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27914802/synthesis-and-in-vitro-antiproliferative-activity-of-c5-benzyl-substituted-2-amino-pyrrolo-2-3-d-pyrimidines-as-potent-hsp90-inhibitors
#9
Ju-Hyeon Lee, Sang Chul Shin, Seon Hee Seo, Young Ho Seo, Nakcheol Jeong, Chan-Wha Kim, Eunice EunKyeong Kim, Gyochang Keum
A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27909956/docking-and-three-dimensional-quantitative-structure-activity-relationship-analyses-of-imidazole-and-thiazolidine-derivatives-as-aurora-a-kinase-inhibitors
#10
Chaeuk Im
Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0...
December 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27881644/suppression-of-adenovirus-replication-by-cardiotonic-steroids
#11
Filomena Grosso, Peter Stoilov, Clifford Lingwood, Martha Brown, Alan Cochrane
: The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yields of four human adenoviruses (HAdV-A31, -B35, and -C5 and a species D conjunctivitis isolate) by at least 2 to 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein hexon is compromised...
February 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27874143/total-synthesis-of-natural-derivatives-and-artificial-analogs-of-13-oxyingenol-and-their-biological-evaluation
#12
Takayuki Ohyoshi, Yuki Tamura, Ichiro Hayakawa, Go Hirai, Yamato Miyazawa, Shota Funakubo, Mikiko Sodeoka, Hideo Kigoshi
We have established an efficient synthetic methodology for the 13-oxyingenol natural derivative (13-oxyingenol-13-dodecanoate-20-hexanoate), featuring a ring-closing olefin metathesis reaction for the "direct" construction of a highly strained inside-outside framework and a Mislow-Evans-type [2,3]-sigmatropic rearrangement for the stereoselective introduction of the hydroxy group at C5. We also synthesized artificial analogs of 13-oxyingenol and ingenol by using our synthetic strategy. In vitro activation assays of protein kinase C (PKC) α and δ revealed that the dodecanoyl group at O13 on 13-oxyingenol analogs had a significant role in PKCδ activation...
December 28, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27846451/sar-study-of-5-alkynyl-substituted-quinazolin-4-3h-ones-as-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#13
Manman Wei, Xi Zhang, Xiang Wang, Zilan Song, Jian Ding, Ling-Hua Meng, Ao Zhang
PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27810992/small-molecule-factor-d-inhibitors-selectively-block-the-alternative-pathway-of-complement-in-paroxysmal-nocturnal-hemoglobinuria-and-atypical-hemolytic-uremic-syndrome
#14
Xuan Yuan, Eleni Gavriilaki, Jane A Thanassi, Guangwei Yang, Andrea C Baines, Steven D Podos, Yongqing Huang, Mingjun Huang, Robert A Brodsky
Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome...
November 3, 2016: Haematologica
https://www.readbyqxmd.com/read/27810412/on-the-value-of-therapeutic-interventions-targeting-the-complement-system-in-acute-myocardial-infarction
#15
REVIEW
Reindert W Emmens, Diana Wouters, Sacha Zeerleder, S Marieke van Ham, Hans W M Niessen, Paul A J Krijnen
The complement system plays an important role in the inflammatory response subsequent to acute myocardial infarction (AMI). The aim of this study is to create a systematic overview of studies that have investigated therapeutic administration of complement inhibitors in both AMI animal models and human clinical trials. To enable extrapolation of observations from included animal studies toward post-AMI clinical trials, ex vivo studies on isolated hearts and proof-of-principle studies on inhibitor administration before experimental AMI induction were excluded...
October 14, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27784126/monitoring-of-complement-activation-biomarkers-and-eculizumab-in-complement-mediated-renal-disorders
#16
C Wehling, O Amon, M Bommer, B Hoppe, K Kentouche, G Schalk, R Weimer, M Wiesener, B Hohenstein, B Tönshoff, R Büscher, H Fehrenbach, Ö-N Gök, M Kirschfink
Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab...
February 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27735867/modulation-of-autophagy-by-a-thioxanthone-decreases-the-viability-of-melanoma-cells
#17
Raquel T Lima, Diana Sousa, Ana M Paiva, Andreia Palmeira, João Barbosa, Madalena Pedro, Madalena M Pinto, Emília Sousa, M Helena Vasconcelos
(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N(10)-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted...
October 10, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27699905/freezing-the-dynamic-gap-for-selectivity-motion-based-design-of-inhibitors-of-the-shikimate-kinase-enzyme
#18
Verónica Prado, Emilio Lence, Paul Thompson, Alastair R Hawkins, Concepción González-Bello
Shikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5-aminoshikimic acid and the natural substrate enhances the selectivity for the H...
December 12, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27692470/complement-activation-by-cholesterol-crystals-triggers-a-subsequent-cytokine-response
#19
Nathalie Niyonzima, Bente Halvorsen, Bjørnar Sporsheim, Peter Garred, Pål Aukrust, Tom Eirik Mollnes, Terje Espevik
In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation...
September 28, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27638863/facin-a-double-edged-sword-of-the-emerging-periodontal-pathogen-filifactor-alocis-a-metabolic-enzyme-moonlighting-as-a-complement-inhibitor
#20
Monika Jusko, Beata Miedziak, David Ermert, Michal Magda, Ben C King, Ewa Bielecka, Kristian Riesbeck, Sigrun Eick, Jan Potempa, Anna M Blom
Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown. We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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