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Topoisomerase

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https://www.readbyqxmd.com/read/28429393/synthesis-and-evaluation-of-thiazolidine-amide-and-n-thiazolyl-amide-fluoroquinolone-derivatives
#1
Isaac Garza, Miranda J Wallace, Dinesh Fernando, Aman Singh, Richard E Lee, Jason S Gerding, Cynthia Franklin, Raghunandan Yendapally
In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8-10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62-6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC50 values of 33...
April 21, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28427827/antiviral-screen-identifies-ev71-inhibitors-and-reveals-camptothecin-target-dna-topoisomerase-1-as-a-novel-ev71-host-factor
#2
Kan Xing Wu, Justin Jang-Hann Chu
Enterovirus 71 (EV71) is one of the causative agents of hand, foot and mouth disease (HFMD) associated with severe neurological disease. EV71's pathogenesis remains poorly understood and the lack of approved antiviral has led to its emergence as a clinically important neurotropic virus. The goals of this study were to: (i) identify novel anti-EV71 compounds that may serve as lead molecules for therapeutics; and (ii) investigate their targets in downstream studies. We screened a 502-compound library of highly purified natural products for anti-EV71 activities in a cell-based immunofluorescence assay that were then confirmed in viral plaque reduction assays...
April 17, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28427215/top2a-ggh-and-pecam1-are-associated-with-hematogenous-lymph-node-and-peritoneal-recurrence-in-stage-ii-iii-gastric-cancer-patients-enrolled-in-the-acts-gc-study
#3
Masanori Terashima, Wataru Ichikawa, Atsushi Ochiai, Koji Kitada, Issei Kurahashi, Shinichi Sakuramoto, Hitoshi Katai, Takeshi Sano, Hiroshi Imamura, Mitsuru Sasako
BACKGROUND: To identify factors related to relapse sites, we carried out an exploratory biomarker analysis of data from the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer study, which is a randomized, controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. PATIENTS AND METHODS: Surgical specimens from 829 patients were retrospectively examined, and 63 genes involved in a variety of biological processes were analyzed by quantitative real-time PCR...
March 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420064/anti-topoisomerase-i-antibodies-in-systemic-lupus-erythematosus-and-potential-association-with-the-presence-of-anti-dsdna-antibodies
#4
M Fredi, I Cavazzana, A Zanola, N Carabellese, A Tincani, M Mahler, F Franceschini
No abstract text is available yet for this article.
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28418653/synthesis-and-biological-evaluation-of-the-first-triple-inhibitors-of-human-topoisomerase-1-tyrosyl-dna-phosphodiesterase-1-tdp1-and-tyrosyl-dna-phosphodiesterase-2-tdp2
#5
Ping Wang, Mohamed S A Elsayed, Caroline B Plescia, Azhar Ravji, Christophe E Redon, Evgeny Kiselev, Christophe Marchand, Olga Zeleznik, Keli Agama, Yves Pommier, Mark Cushman
Tdp1 and Tdp2 are two tyrosyl-DNA phosphodiesterases that can repair damaged DNA resulting from topoisomerase inhibitors and a variety of other DNA-damaging agents. Both Tdp1 and Tdp2 inhibition could hypothetically potentiate the cytotoxicities of topoisomerase inhibitors. This study reports the successful structure-based design and synthesis of new 7-azaindenoisoquinolines that act as triple inhibitors of Top1, Tdp1, and Tdp2. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures establish that modification of the lactam side chain of the 7-azaindenoisoquinolines can modulate their inhibitory potencies and selectivities vs Top1, Tdp1, and Tdp2...
April 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28417947/pro-angiogenic-effects-of-low-dose-ethoxidine-in-a-murine-model-of-ischemic-hindlimb-correlation-between-ethoxidine-levels-and-increased-activation-of-the-nitric-oxide-pathway
#6
Nicolas Clere, Kim Hung Thien To, Samuel Legeay, Samuel Bertrand, Jean Jacques Helesbeux, Olivier Duval, Sébastien Faure
Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10(-9) M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10(-9) M...
April 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28417283/bis-anthracycline-wp760-abrogates-melanoma-cell-growth-by-transcription-inhibition-p53-activation-and-igf1r-downregulation
#7
Magdalena Olbryt, Aleksandra Rusin, Izabela Fokt, Anna Habryka, Patrycja Tudrej, Sebastian Student, Aleksander Sochanik, Rafał Zieliński, Waldemar Priebe
Anthracycline chemotherapeutics, e.g. doxorubicin and daunorubicin, are active against a broad spectrum of cancers. Their cytotoxicity is mainly attributed to DNA intercalation, interference with topoisomerase activity, and induction of double-stranded DNA breaks. Since modification of anthracyclines can profoundly affect their pharmacological properties we attempted to elucidate the mechanism of action, and identify possible molecular targets, of bis-anthracycline WP760 which previously demonstrated anti-melanoma activity at low nanomolar concentrations...
April 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28415835/the-role-of-chemotherapy-in-unresectable-or-metastatic-adenocarcinoma-of-the-stomach-and-gastroesophageal-junction
#8
Mustafa Bozkurt, Fatemeh G Amlashi, Mariela Blum Murphy
Gastric cancer including gastro-esophageal junction adenocarcinomas are most challenging and deadly cancers of the gastrointestinal tract. Gastric cancer has a fatality-to-case ratio of 0.66, translating that nearly two thirds of newly diagnosed patients will have disseminated disease and in need of systemic therapy (1). Advanced gastric adenocarcinoma (AGC) is a heterogenous disease with differences in geographical distribution, histopathology, and molecular subtypes. Fluoropyrimidines (5-FU, S-1, and capecitabine), platinum compounds (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), and the topoisomerase inhibitory irinotecan are active drugs against AGC...
April 14, 2017: Minerva Chirurgica
https://www.readbyqxmd.com/read/28415827/camptothecin-resistance-is-determined-by-the-regulation-of-topoisomerase-i-degradation-mediated-by-ubiquitin-proteasome-pathway
#9
Koji Ando, Ankur K Shah, Vibhu Sachdev, Benjamin P Kleinstiver, Julian Taylor-Parker, Moira M Welch, Yiheng Hu, Ravi Salgia, Forest M White, Jeffrey D Parvin, Al Ozonoff, Lucia E Rameh, J Keith Joung, Ajit K Bharti
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415741/enhancement-of-radiosensitivity-by-the-novel-anticancer-quinolone-derivative-vosaroxin-in-preclinical-glioblastoma-models
#10
Giovanni Luca Gravina, Andrea Mancini, Claudia Mattei, Flora Vitale, Francesco Marampon, Alessandro Colapietro, Giulia Rossi, Luca Ventura, Antonella Vetuschi, Ernesto Di Cesare, Judith A Fox, Claudio Festuccia
PURPOSE: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. The activity of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, was investigated in GBM preclinical models as a single agent and combined with radiotherapy (RT). RESULTS: Vosaroxin showed antitumor activity in clonogenic survival assays, with IC50 of 10-100 nM, and demonstrated radiosensitization. Combined treatments exhibited significantly higher γH2Ax levels compared with controls...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415021/in-vitro-investigation-of-metabolic-profiling-of-a-potent-topoisomerase-inhibitors-fluorescein-hydrazones-flhs-in-rlms-by-lc-ms-ms
#11
A F M Motiur Rahman, Nasser S Al-Shakliah, Wencui Yin, Adnan A Kadi
Metabolic profiling of newly reported two topoisomerase inhibitors namely fluorescein hydrazones (FLHs) were studied in rat liver microsomes (RLMs) and the data were acquired in a liquid chromatography (LC) ion trap mass spectrometry. (E)-3',6'-dihydroxy-2-((2-nitrobenzylidene)amino)spiro[isoindoline-1,9'-xanthen]-3-one (1) was bio-transformed into two mono-hydroxylated, one double hydroxylated and a tetra hydroxylated metabolites, on the other hand, (Z)-3',6'-dihydroxy-2-((2-oxoindolin-3-ylidene)amino)spiro[isoindoline-1,9'-xanthen]-3-one (2) was bio-transformed into eight possible metabolites by cleavage reduction, hydroxylation, cleavage reduction together with hydroxylated and azo-reduction in RLMs in presence of NADPH-generating system...
April 10, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28414321/an-orthogonal-single-molecule-experiment-reveals-multiple-attempt-dynamics-of-type-ia-topoisomerases
#12
Kathryn H Gunn, John F Marko, Alfonso Mondragón
Topoisomerases are enzymes that are involved in maintaining the topological state of cellular DNA. Their dynamic characteristics remain poorly understood despite numerous structural, biophysical and biochemical studies. Recent single-molecule experiments revealed that an important feature of the type IA topoisomerase mechanism is the presence of pauses between relaxation events. However, these experiments could not determine whether the protein remains DNA bound during the pauses or what relationship may exist between protein domain movements and topological changes in the DNA...
April 17, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28412545/dna-topoisomerase-1-prevents-r-loop-accumulation-to-modulate-auxin-regulated-root-development-in-rice
#13
Sarfraz Shafiq, Chunli Chen, Jing Yang, Lingling Cheng, Fei Ma, Emilie Widemann, Qianwen Sun
R-loop structures (RNA:DNA hybrids) have important functions in many biological processes, including transcriptional regulation and genome instability among diverse organisms. DNA Topoisomerase 1 (TOP1), an essential manipulator of DNA topology during RNA transcription and DNA replication processes, can prevent R-loop accumulation by removing the positive and negative DNA supercoiling that is made by RNA polymerases during transcription. TOP1 is required for plant development, but little is known about its function in preventing co-transcriptional R-loops in different plant biological processes...
April 12, 2017: Molecular Plant
https://www.readbyqxmd.com/read/28412222/targeted-drug-distribution-in-tumor-extracellular-fluid-of-gd2-expressing-neuroblastoma-patient-derived-xenografts-using-sn-38-loaded-nanoparticles-conjugated-to-the-monoclonal-antibody-3f8
#14
Carles Monterrubio, Sonia Paco, Nagore G Olaciregui, Guillem Pascual-Pasto, Monica Vila-Ubach, Maria Cuadrado-Vilanova, M Mar Ferrandiz, Helena Castillo-Ecija, Romina Glisoni, Nataliya Kuplennik, Achim Jungbluth, Carmen de Torres, Cinzia Lavarino, Nai-Kong V Cheung, Jaume Mora, Alejandro Sosnik, Angel M Carcaboso
Neuroblastoma is a pediatric solid tumor with high expression of the tumor associated antigen disialoganglioside GD2. Despite initial response to induction therapy, nearly 50% of high-risk neuroblastomas recur because of chemoresistance. Here we encapsulated the topoisomerase-I inhibitor SN-38 in polymeric nanoparticles (NPs) surface-decorated with the anti-GD2 mouse mAb 3F8 at a mean density of seven antibody molecules per NP. The accumulation of drug-loaded NPs targeted with 3F8 versus with control antibody was monitored by microdialysis in patient-derived GD2-expressing neuroblastoma xenografts...
April 12, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28409362/the-antibacterial-agent-moxifloxacin-inhibits-virulence-factors-of-candida-albicans-through-multitargeting
#15
Ashwini Jadhav, Bhagyashree Bansode, Datta Phule, Amruta Shelar, Rajendra Patil, Wasudev Gade, Kiran Kharat, Sankunny Mohan Karuppayil
Fluoroquinolines are broad spectrum fourth generation antibiotics. Some of the Fluoroquinolines exhibit antifungal activity. We are reporting the potential mechanism of action of a fluoroquinoline antibiotic, moxifloxacin on the growth, morphogenesis and biofilm formation of the human pathogen Candida albicans. Moxifloxacin was found to be Candidacidal in nature. Moxifloxacin seems to inhibit the yeast to Hyphal morphogenesis by affecting signaling pathways. It arrested the cell cycle of C. albicans at S phase...
May 2017: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28406300/synthesis-and-characterization-of-tetrahydropyran-based-bacterial-topoisomerase-inhibitors-with-antibacterial-activity-against-gram-negative-bacteria
#16
Jean-Philippe Surivet, Cornelia Zumbrunn, Thierry Bruyère, Daniel Bur, Christopher Kohl, Hans H Locher, Peter Seiler, Eric A Ertel, Patrick Hess, Michel Enderlin-Paput, Stéphanie Enderlin-Paput, Jean-Christophe Gauvin, Azely Mirre, Christian Hubschwerlen, Daniel Ritz, Georg Rueedi
There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multi-drug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules towards difficult-to-treat Gram-negative pathogens...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28406299/discovery-and-optimization-of-isoquinoline-ethyl-ureas-as-antibacterial-agents
#17
Philippe Panchaud, Thierry Bruyère, Anne-Catherine Blumstein, Daniel Bur, Alain Chambovey, Eric A Ertel, Markus Gude, Christian Hubschwerlen, Loïc Jacob, Thierry Kimmerlin, Thomas Pfeifer, Lars Prade, Peter Seiler, Daniel Ritz, Georg Rueedi
Our strategy to combat resistant bacteria consisted in targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28401446/liposomal-irinotecan-a-review-in-metastatic-pancreatic-adenocarcinoma
#18
Yvette N Lamb, Lesley J Scott
Intravenous liposomal irinotecan injection (Onivyde(®)) is approved for use in combination with 5-fluorouracil and leucovorin (5-FU/LV) in patients with metastatic pancreatic adenocarcinoma that has progressed following gemcitabine-based therapy. Liposomal irinotecan is a liposome-encapsulated formulation of the topoisomerase-1 inhibitor irinotecan, developed to overcome the pharmacological and clinical limitations of non-liposomal irinotecan. In the pivotal multinational, phase III NAPOLI-1 trial in patients with metastatic pancreatic adenocarcinoma that had progressed following gemcitabine-based therapy, liposomal irinotecan in combination with 5-FU/LV significantly prolonged median overall survival (OS; primary endpoint) and median progression-free survival (PFS) at the time of the primary analysis (after 313 events) and final analysis (after 382 events) compared with 5-FU/LV control therapy...
April 11, 2017: Drugs
https://www.readbyqxmd.com/read/28399679/an-overview-of-quinoline-as-a-privileged-scaffold-in-cancer-drug-discovery
#19
Robert Musiol
The concept of privileged structures is well known and is often used in the process of drug design and development. Although its assumptions are not clear, its overall usefulness remains high. Various substructures have been identified as privileged and quinoline is a prime example of such a structure. Areas covered: Quinoline drugs that are currently approved or under clinical investigation were reviewed based on a literature search. Their modes of action and outcomes during clinical research are discussed...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28398568/deacetylation-of-topoisomerase-i-is-an-important-physiological-function-of-e-coli-cobb
#20
Qingxuan Zhou, Yan Ning Zhou, Ding Jun Jin, Yuk-Ching Tse-Dinh
Escherichia coli topoisomerase I (TopA), a regulator of global and local DNA supercoiling, is modified by Nε-Lysine acetylation. The NAD+-dependent protein deacetylase CobB can reverse both enzymatic and non-enzymatic lysine acetylation modification in E. coli. Here, we show that the absence of CobB in a ΔcobB mutant reduces intracellular TopA catalytic activity and increases negative DNA supercoiling. TopA expression level is elevated as topA transcription responds to the increased negative supercoiling...
April 8, 2017: Nucleic Acids Research
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