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https://www.readbyqxmd.com/read/28240185/design-synthesis-and-molecular-docking-of-1-cyclopropyl-6-fluoro-4-oxo-7-4-2-4-substituted-phenyl-2-substituted-ethyl-1-piperazinyl-1-4-dihydroquinoline-3-carboxylic-acid-as-an-antimicrobial-agents
#1
Mehul M Patel, Laxman J Patel
BACKGROUND: Quinolone scaffold are widely used for synthesis of number of medicinal compounds with variety of biological activity. In view of the reported antimicrobial activity of various fluoroquinolones, the structure activity studies of various substituted quinolones, which proved the importance of the C-7 substituents to exhibit potent antimicrobial activities. OBJECTIVE: Based on the structural activity relationship at C-7 position it was rationalized to design and synthesize new quinolone derivatives with increasing bulk at C-7 position of the main 6-fluoroquinolone scaffold...
February 24, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28237034/machine-learning-and-docking-models-for-mycobacterium-tuberculosis-topoisomerase-i
#2
Sean Ekins, Adwait Anand Godbole, György Kéri, Lászlo Orfi, János Pato, Rajeshwari Subray Bhat, Rinkee Verma, Erin K Bradley, Valakunja Nagaraja
There is a shortage of compounds that are directed towards new targets apart from those targeted by the FDA approved drugs used against Mycobacterium tuberculosis. Topoisomerase I (Mttopo I) is an essential mycobacterial enzyme and a promising target in this regard. However, it suffers from a shortage of known inhibitors. We have previously used computational approaches such as homology modeling and docking to propose 38 FDA approved drugs for testing and identified several active molecules. To follow on from this, we now describe the in vitro testing of a library of 639 compounds...
March 2017: Tuberculosis
https://www.readbyqxmd.com/read/28236767/triggering-autophagic-cell-death-with-a-di-manganese-ii-developmental-therapeutic
#3
Creina Slator, Zara Molphy, Vickie McKee, Andrew Kellett
There is an unmet need for novel metal-based chemotherapeutics with alternative modes of action compared to clinical agents such as cisplatin and metallo-bleomycin. Recent attention in this field has focused on designing intracellular ROS-mediators as powerful cytotoxins of human cancers and identifying potentially unique toxic mechanisms underpinning their utility. Herein, we report the developmental di-manganese(II) therapeutic [Mn2(μ-oda)(phen)4(H2O)2][Mn2(μ-oda)(phen)4(oda)2]·4H2O (Mn-Oda) induces autophagy-promoted apoptosis in human ovarian cancer cells (SKOV3)...
February 4, 2017: Redox Biology
https://www.readbyqxmd.com/read/28231233/association-of-topoisomerase-ii-top2a-and-dual-specificity-phosphatase-6-dusp6-single-nucleotide-polymorphisms-with-radiation-treatment-response-and-prognosis-of-lung-cancer-in-han-chinese
#4
Tian-Lu Wang, Yang-Wu Ren, He-Tong Wang, Hong Yu, Yu-Xia Zhao
BACKGROUND Mutations of DNA topoisomerase II (TOP2A) are associated with chemotherapy resistance, whereas dual-specificity phosphatase 6 (DUSP6) negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily to control cell proliferation. This study assessed TOP2A and DUSP6 single nucleotide polymorphisms (SNPs) in non-small cell lung cancer (NSCLC) patients for association with chemoradiotherapy responses and prognosis. MATERIAL AND METHODS A total of 140 Chinese patients with histologically confirmed NSCLC were enrolled and subjected to genotyping of TOP2A rs471692 and DUSP6 rs2279574 using Taqman PCR...
February 23, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28229819/dabigatran-aggravates-topoisomerase-i-peptide-loaded-dendritic-cells-induced-lung-and-skin-fibrosis
#5
Heena Mehta, Philippe-Olivier Goulet, Jade Desjardins, Gemma Pérez, Martial Koenig, Jean-Luc Senécal, Marika Sarfati
OBJECTIVES: Dysregulated coagulation cascade has been implicated in development of fibrosis in systemic sclerosis (SSc). Thrombin, a key mediator of the coagulation pathway, has both proinflammatory and procoagulant properties. Here, we evaluated the efficacy of oral dabigatran, a direct thrombin inhibitor, on topoisomerase I dendritic cells (TOPOIA DCs)-induced lung and skin fibrosis, an experimental model of SSc. METHODS: Mice were repeatedly immunized with TOPOIA DCs...
February 8, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28223393/novel-bacterial-topoisomerase-inhibitors-with-potent-broad-spectrum-activity-against-drug-resistant-bacteria
#6
Cédric Charrier, Anne-Marie Salisbury, Victoria J Savage, Thomas Duffy, Emmanuel Moyo, Nathan Chaffer-Malam, Nicola Ooi, Rebecca Newman, Jonathan Cheung, Richard Metzger, David McGarry, Mark Pichowicz, Ralph Sigerson, Ian R Cooper, Gary Nelson, Hayley S Butler, Mark Craighead, Andrew J Ratcliffe, Stuart A Best, Neil R Stokes
The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecules. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28217959/anti-rnpc3-antibodies-as-a-marker-of-cancer-associated-scleroderma
#7
Ami A Shah, George Xu, Antony Rosen, Laura K Hummers, Fredrick M Wigley, Stephen J Elledge, Livia Casciola-Rosen
INTRODUCTION: Prior studies have demonstrated an increased risk of cancer-associated scleroderma in patients with RNA polymerase III (POL) autoantibodies and in patients negative for anti-centromere (CENP), anti-topoisomerase-1 (TOPO), and anti-POL antibodies (referred to as CENP/TOPO/POL (CTP)-Negative). In a recent study of 16 CTP-negative scleroderma patients with coincident cancer, we found that 25% had autoantibodies to RNPC3, a member of the minor spliceosome complex. In this investigation, we validated the relationship between anti-RNPC3 antibodies and cancer and examined the associated clinical phenotype in a large sample of scleroderma patients...
February 19, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28214612/dynamic-organization-of-mitotic-chromosomes
#8
REVIEW
Kazuhisa Kinoshita, Tatsuya Hirano
The assembly of rod-shaped chromosomes during mitosis is an essential prerequisite for faithful segregation of genetic information into daughter cells. Despite the long history of chromosome research, it is only recently that we have acquired powerful approaches and crucial tools that help to unlock the secret of this seemingly complex process. In particular, in vitro assays, mammalian genetics, Hi-C analyses and computer simulations have provided valuable information during the past two years. These studies are now beginning to elucidate how the core components of mitotic chromosomes, namely, histones, topoisomerase IIα and condensins, cooperate with each other to convert very long stretches of DNA into rod-shaped chromosomes...
February 16, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28214203/prognostic-value-of-survivin-and-dna-topoisomerase-ii%C3%AE-in-diffuse-and-anaplastic-astrocytomas
#9
R K Varughese, A J Skjulsvik, S H Torp
Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase IIα (TIIα) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs...
January 21, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28209630/inhibition-of-phosphodiesterase-4-pde4-reduces-dermal-fibrosis-by-interfering-with-the-release-of-interleukin-6-from-m2-macrophages
#10
Christiane Maier, Andreas Ramming, Christina Bergmann, Rita Weinkam, Nicolai Kittan, Georg Schett, Jörg H W Distler, Christian Beyer
OBJECTIVES: To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc). METHODS: We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4...
February 16, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28206967/calcium-regulatory-proteins-as-modulators-of-chemotherapy-in-human-neuroblastoma
#11
Ana-Maria Florea, Elizabeth Varghese, Jennifer E McCallum, Safa Mahgoub, Irfan Helmy, Sharon Varghese, Neha Gopinath, Steffen Sass, Fabian J Theis, Guido Reifenberger, Dietrich Büsselberg
Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca2+]i)...
February 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28206703/toxicological-evaluation-of-the-topoisomerase-inhibitor-etoposide-in-the-model-animal-caenorhabditis-elegans-and-3t3-l1-normal-murine-cells
#12
So Young Lee, Joo Yeon Kim, Yu-Jin Jung, Kyungsu Kang
Etoposide, a topoisomerase II inhibitor, has been widely used as a clinical anticancer drug to treat diverse cancer patients. Since not only rapidly dividing cancer cells but also the cells of normal human tissues and every living organism in environmental ecosystems have topoisomerases, it is crucial to study the toxicity of etoposide in other organisms in addition to cancer cells. In this study, we evaluated the toxicity of etoposide in both a soil nematode, Caenorhabditis elegans, and 3T3-L1 normal murine cells...
February 16, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28204881/genetic-evidence-for-functional-interaction-of-smc5-6-complex-and-top1-with-spatial-frequency-of-replication-origins-required-for-maintenance-of-chromosome-stability
#13
Ragini Rai, Shikha Laloraya
Replication of linear chromosomes is facilitated by firing of multiple replication origins that ensures timely duplication of the entire chromosome. The Smc5/6 complex is thought to play an important role in replication by its involvement in the restart of collapsed replication forks. Here, we present genetic evidence for functional interaction between replication origin distribution and two subunits of the Smc5/6 complex, Smc6 and Mms21, as well as Top1. An artificial chromosome that has a long arm having low origin density (5ori∆YAC) is relatively unstable compared to the YAC having normal origin distribution in wild-type cells, but is partially stabilized in smc6-56 and top1∆ mutants...
February 16, 2017: Current Genetics
https://www.readbyqxmd.com/read/28199696/spartan-deficiency-causes-accumulation-of-topoisomerase-1-cleavage-complexes-and-tumorigenesis
#14
Reeja S Maskey, Karen S Flatten, Cynthia J Sieben, Kevin L Peterson, Darren J Baker, Hyun-Ja Nam, Myoung Shin Kim, Thomas C Smyrk, Yusuke Kojima, Yuka Machida, Annyoceli Santiago, Jan M van Deursen, Scott H Kaufmann, Yuichi J Machida
No abstract text is available yet for this article.
February 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28195382/contribution-of-atm-and-atr-kinase-pathways-to-p53-mediated-response-in-etoposide-and-methyl-methanesulfonate-induced-dna-damage
#15
Bin Sun, Susan M Ross, Sean Rowley, Yeyejide Adeleye, Rebecca A Clewell
p53 is a key integrator of cellular response to DNA damage, supporting post-translational repair and driving transcription-mediated responses including cell cycle arrest, apoptosis, and repair. DNA damage sensing kinases recognize different types of DNA damage and initiate specific responses through various post-translational modifications of p53. This study evaluated chemical specificity of the p53 pathway response by manipulating p53 or its upstream kinases and assessing the effect on DNA damage and cellular responses to prototype chemicals: etoposide (ETP, topoisomerase II inhibitor) and methyl methane sulfonate (MMS, alkylating agent)...
February 14, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28185035/anthracycline-chemotherapy-and-cardiotoxicity
#16
John V McGowan, Robin Chung, Angshuman Maulik, Izabela Piotrowska, J Malcolm Walker, Derek M Yellon
Anthracycline chemotherapy maintains a prominent role in treating many forms of cancer. Cardiotoxic side effects limit their dosing and improved cancer outcomes expose the cancer survivor to increased cardiovascular morbidity and mortality. The basic mechanisms of cardiotoxicity may involve direct pathways for reactive oxygen species generation and topoisomerase 2 as well as other indirect pathways. Cardioprotective treatments are few and those that have been examined include renin angiotensin system blockade, beta blockers, or the iron chelator dexrazoxane...
February 9, 2017: Cardiovascular Drugs and Therapy
https://www.readbyqxmd.com/read/28182813/second-malignant-neoplasms-in-childhood-cancer-survivors-treated-in-a-tertiary-paediatric-oncology-centre
#17
Jia Wei Lim, Frances Sh Yeap, Yiong Huak Chan, Allen Ej Yeoh, Thuan Chong Quah, Poh Lin Tan
Introduction: One of the most feared complications of childhood cancer treatment is second malignant neoplasms (SMNs). This study evaluates the incidence, risk factors and outcomes of SMNs in a tertiary paediatric oncology centre in Singapore. Materials and Methods: A retrospective review was conducted on patients diagnosed with childhood cancer under age 21 and treated at the National University Hospital, Singapore, from January 1990 to 15 April 2012. Case records of patients with SMNs were reviewed. Results: We identified 1124 cases of childhood cancers with a median follow-up of 3...
January 2017: Annals of the Academy of Medicine, Singapore
https://www.readbyqxmd.com/read/28182434/a-model-based-approach-to-assessing-the-importance-of-intracellular-binding-sites-in-doxorubicin-disposition
#18
Ilse R Dubbelboer, Elsa Lilienberg, Erik Sjögren, Hans Lennernäs
Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (Kp,t), could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model...
February 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28182079/immunocytoexpression-profile-of-proexc-in-smears-interpreted-as-asc-us-asc-h-and-cervical-intraepithelial-lesion
#19
Zeynep Tosuner, İlknur Türkmen, Sema Arici, Cavide Sönmez, Seval Turna, Öykü Onaran
AIMS: We aimed to investigate the immunocytoexpression profiles of a novel assay ProEx C for topoisomerase II alpha (TOP2A) and minichromosome maintenance protein 2 (MCM2) in abnormal interpreted smears. SETTINGS AND DESIGN: Screening programs with Papanicolaou smear and high risk group human papilloma virus testing have yielded a dramatic reduction of cervical cancer incidence. However, both of these tests have limited specificity for the detection of clinically significant cervical high grade lesions...
January 2017: Journal of Cytology
https://www.readbyqxmd.com/read/28180300/epigenetic-changes-in-histone-acetylation-underpin-resistance-to-the-topoisomerase-i-inhibitor-irinotecan
#20
Cornelia Meisenberg, Mohamed E Ashour, Lamia El-Shafie, Chunyan Liao, Adam Hodgson, Alice Pilborough, Syed A Khurram, Jessica A Downs, Simon E Ward, Sherif F El-Khamisy
No abstract text is available yet for this article.
February 17, 2017: Nucleic Acids Research
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