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Öğe 1H-benzimidazole derivatives as mammalian DNA topoisomerase I inhibitors(Acta Biochimica Polonica, 2007) Alpan, A. Selcen; Gunesi, H. Sernih; Topcu, ZekiBenzimidazole is one of the most important heterocyclic groups manifesting various biological properties, such as antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Several benzimidazole derivatives are also active as inhibitors of type I DNA topoisomerases. In this study, three 1H-benzimidazole derivatives with different electronic characteristics at position 5-, namely 5-chloro-4-(1H-benzimidazole-2-yl)phenoI (Cpd I), 5-methyl-4-(1H-benzimidazole-2-yl)phenol (Cpd II) and 4-(1H-benzimidazole-2-yl)phenol (Cpd III), were synthesized and evaluated for their effects on mammalian type I DNA topoisomerase activity using quantitative in vitro plasmid supercoil relaxation assays. For the structure elucidation of the compounds, melting points, UV, IR, H-1 NMR, C-13 NMR, mass spectral data and elemental analyses were interpreted. Among the compounds, 5-methyl-4-(1H-benzimidazole-2-yl)phenoI (Cpd II) manifested relatively potent topoisomerase I inhibition.Öğe Anticancer and Multidrug Resistance-Reversal Effects of Solanidine Analogs Synthetized from Pregnadienolone Acetate(Mdpi, 2014) Zupko, Istvan; Molnar, Judit; Rethy, Borbala; Minorics, Renata; Frank, Eva; Woelfling, Janos; Molnar, Joseph; Ocsovszki, Imre; Topcu, Zeki; Bito, Tamas; Puskas, Laszlo G.A set of solanidine analogs with antiproliferative properties were recently synthetized from pregnadienolone acetate, which occurs in Nature. The aim of the present study was an in vitro characterization of their antiproliferative action and an investigation of their multidrug resistance-reversal activity on cancer cells. Six of the compounds elicited the accumulation of a hypodiploid population of HeLa cells, indicating their apoptosis-inducing character, and another one caused cell cycle arrest at the G2/M phase. The most effective agents inhibited the activity of topoisomerase I, as evidenced by plasmid supercoil relaxation assays. One of the most potent analogs down-regulated the expression of cell-cycle related genes at the mRNA level, including tumor necrosis factor alpha and S-phase kinase-associated protein 2, and induced growth arrest and DNA damage protein 45 alpha. Some of the investigated compounds inhibited the ABCB1 transporter and caused rhodamine-123 accumulation in murine lymphoma cells transfected by human MDR1 gene, expressing the efflux pump (L5178). One of the most active agents in this aspect potentiated the antiproliferative action of doxorubicin without substantial intrinsic cytostatic capacity. The current results indicate that the modified solanidine skeleton is a suitable substrate for the rational design and synthesis of further innovative drug candidates with anticancer activities.Öğe Anticancer Properties of Natural Products(Hindawi Publishing Corporation, 2015) Zupko, Istvan; Jaeger, Walter; Topcu, Zeki; Wu, Chin-ChungÖğe Apoptotic and Necrotic Cell Percentages in Kidney Cells from Rats Exposed to Magnetic Field(Taylor & Francis Inc, 2009) Emre, Mustafa; Cetiner, Salih; Zencir, Sevil; Topcu, ZekiÖğe Apoptotic and Necrotic Cell Percentages in Kidney Cells from Rats Exposed to Magnetic Field(Taylor & Francis Inc, 2009) Emre, Mustafa; Cetiner, Salih; Zencir, Sevil; Topcu, ZekiÖğe Biological Activity of 1-Aryl-3-phenethylamino-1-propanone Hydrochlorides and 3-Aroyl-4-aryl-1-phenethyl-4-piperidinols on PC-3 Cells and DNA Topoisomerase I Enzyme(Walter De Gruyter Gmbh, 2010) Mete, Ebru; Gul, Halise Inci; Canturk, Pakize; Topcu, Zeki; Pandit, Bulbul; Gul, Mustafa; Li, Pui-KaiA number of studies reported Mannich bases to manifest antimicrobial, cytotoxic, anticancer, anti-inflammatory, and anticonvulsant activities. A considerable number of therapeutically important cytotoxic compounds are active on DNA topoisomerases that regulate the DNA topology. In the present study we evaluated the biological activity of mono-Mannich bases, 1-aryl-3-phenethylamino-1-propanone hydrochlorides (1a-10a), and semicyclic mono-Mannich bases, 3-aroyl-4-aryl-1-phenethyl-4-piperidinols (1b-9b), synthesized in our laboratory. We employed androgen-independent human prostate cancer cells (PC-3) to assess the cytotoxicity of the compounds and extended the biological activity evaluation to cover supercoil relaxation assays of mammalian type I topoisomerases. Our results showed that the compounds had cytotoxicity within the 8.2-32.1 mu m range, while two compounds gave rise to a comparable average value in topo I interference of 42% and 40% for 10a (with a hydroxy substituent on the phenyl ring from mono-Mannich bases) and 5b (with a fluoro substituent on the phenyl ring from the semicyclic mono-Mannich base series, piperidinols), respectively.Öğe Biological activity of bis-benzimidazole derivatives on DNA topoisomerase I and HeLa, MCF7 and A431 cells(Taylor & Francis Ltd, 2009) Alpan, A. Selcen; Zencir, Sevil; Zupko, Istvan; Coban, Gunes; Rethy, Borbala; Gunes, H. Semih; Topcu, ZekiBenzimidazoles of both natural and synthetic sources are the key components of many bio-active compounds. Several reports have shown antifungal, antiviral, H-2 receptor blocker and antitumor activities for benzimidazoles and their derivatives. In this study, we synthesized twelve bis-benzimidazole derivatives by selecting di(1H-benzo[d]imidazol-2-yl)methane as the main compound. The numbers of carbons at 2 positions of bis-benzimidazole derivatives were changed from 1 to 4, and derivatives were synthesized with methyl substitutions at 5-and/or6-positions. The compounds were screened via in vitro plasmid superciol relaxation assays using mammalian DNA topoisomerase I and cytostatic assays were carried out against HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells for selected derivatives. Our results suggest that the malonic acid derivatives of bis-benzimidazoles, namely, bis(5-methyl-1H-benzo[d]imidazol-2yl)methane and bis(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methane, were remarkably active compounds in interfering with DNA topoisomerase I and the former compound was also found to be cytotoxic against MCF7 and A431 cells. The inhibitory effects obtained with these derivatives are significant as these compounds can be potential sources of anticancer agents.Öğe Che1/AATF interacts with subunits of the histone acetyltransferase core module of SAGA complexes(Public Library Science, 2017) Caliskan, Gizem; Baris, Ikbal C.; Ayaydin, Ferhan; Dobson, Melanie J.; Senarisoy, Muge; Boros, Imre M.; Topcu, Zeki; Zencir, SevilGeneral Control Non-derepressible 5 (GCN5) and Alteration/Deficiency in Activation 2 and 3 proteins (ADA2 and ADA3, respectively) are subunits of the Histone AcetylTransferase (HAT) module of SAGA-and ATAC-type co-activators. We previously reported four new interacting partners of human ADA3 identified by screening a human fetal brain cDNA library using yeast two hybrid technology. One of these partners was Apoptosis-Antagonizing Transcription Factor (AATF), also known as Che-1, an RNA polymerase II-binding protein with a number of roles in different cellular processes including regulation of transcription, cell proliferation, cell cycle control, DNA damage responses and apoptosis. Che-1/AATF is a potential therapeutic target for cancer treatments. In this study, we aimed to identify whether besides ADA3, other components of the HAT modules of SAGA and ATAC complexes, human ADA2 and GCN5 also interact with Che-1/AATF. Co-immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins in human cells and yeast two-hybrid assays to delineate domains in the ADA2 and GCN5 proteins required for these interactions. These findings provide new insights into the pathways regulated by ADA-containing protein complexes.Öğe Comparative Cytochrome P450-1A1, -2A6, -2B6, -2C, -2D6, -2E1, -3A5 and -4B1 expressions in human larynx tissue analysed at mRNA level(John Wiley & Sons Ltd, 2006) Sarikaya, Devrim; Bilgen, Cem; Kamataki, Tetsuya; Topcu, ZekiThe metabolic activation of numerous exogenous and endogenous chemicals is catalysed by cytochrome P450 enzymes (CYPs). The aim of this study was to analyse the expression of the individual forms of CYP at the mRNA level in human larynx and quantitatively to compare their expressions in human liver, the main in organ of CYP expression. Individual forms of CYP mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primers for the CYPs -1A1, -1A2, -2A6,-2B6,-2C, -2D6, -2E1, -3A3/4 ,-3A5, -3A7 and 4B1. An RNA competitor of known copy number, covering the primer sequences necessary to amplify the entire object CYPs within a single molecule, was used as reference. This study reports a consistent detection of mRNAs for the CYPs -1A1, -2A6, -2B6, -2C, -2D6, -2E1, -3A5 and -4B1 in the human larynx tissue. The data indicate that the human larynx highly resembles the lung tissue in CYP content, as a comparable subset of CYP mRNAs was detected in the larynx previously reported for human lung with the exception of CYP1A2. The results are discussed in quantitative ratios of the detected CYP mRNAs in relation to the hepatic CYP expression. Copyright (c) 2006 John Wiley & Sons, Ltd.Öğe Critical time point for apoptotic cell death in an experimental ischemia/reperfusion model and the effect of N-acetylcystein(Walter De Gruyter Gmbh, 2017) Ozsarlak-Sozer, Gonen; Emre, Mustafa; Demirkol, Serhat; Acikalin, Arbil; Cetiner, Salih; Topcu, Zeki; Demir-Dora, DevrimObjective: Kidney transplantation is an important treatment option in end stage renal failure. Tissue death may be an important problem when a kidney is removed from a cadaver and transported to a donor a long distance away. The purpose of this study is to determine the critical time point for apoptotic cell death in a renal ischemia/reperfusion model and determine the effects of N-acetylcystein on apoptosis induced by ischemia injury. Methods: Apoptotic cell death after induced renal ischemia followed by reperfusion, was estimated in a group of Wistar albino rats by immunoflourescence and ELISA techniques. N-acetylcystein, an antioxidant agent, was given to the rats to study the effect on apoptosis. Tissues were examined immunohistochemically at 0, 1 h, 24 h, 5 days and 10 days for detection of apoptotic cells. Results: Our results showed that an ischemia for 60 min followed by reperfusion for 60 min triggered apoptosis. Moreover, N-acetylcystein significantly diminished both the ischemia/reperfusion damage and apoptosis. Conclusion: We anticipate our results would be important for kidney transplantation in estimating the critical time point for apoptosis and administration of N-acetylcystein prior to removal of the organ may be important in delaying the onset of apoptosis.Öğe Cytotoxic activity of 4 '-hydroxychalcone derivatives against Jurkat cells and their effects on mammalian DNA topoisomerase I(Taylor & Francis Ltd, 2009) Gul, Halise Inci; Cizmecioglu, Murat; Zencir, Sevil; Gul, Mustafa; Canturk, Pakize; Atalay, Mustafa; Topcu, ZekiChalcones (1,3-diaryl-2-propen-1-ones) are alpha, beta-unsaturated ketones with cytotoxic and anticancer properties. Several reports have shown that compounds with cytotoxic properties may also interfere with DNA topoisomerase functions. Five derivatives of 4'-hydroxychalcones were examined for cytotoxicity against transformed human T (Jurkat) cells as well as plasmid supercoil relaxation experiments using mammalian DNA topoisomerase I. The compounds were 3-phenyl-1-(4'-hydroxyphenyl)-2-propen-1-one (I), 3-(p-methylphenyl)-1-(4'-hydroxyphenyl)-2-propen-1-one (II), 3-(p-methoxyphenyl)-1-(4'-hydroxyphenyl)-2-propen-1-one (III), 3-(p-chlorophenyl)-1-(4'-hydroxyphenyl)-2-propen-1-one (IV), and 3-(2- thienyl)-1-(4'-hydroxyphenyl)-2-propen-1-one (V). The order of the cytotoxicity of the compounds was; IV > III > II > I > V. Compound IV, had the highest Hammett and log P values (0.23 and 4.21, respectively) and exerted both highest cytotoxicity and strongest DNA topoisomerase I inhibition. Compounds I and II gave moderate interference with the DNA topoisomerase I while III & V did not interfere with the enzyme.Öğe The Effects of Arolycoricidine and Narciprimine on Tumor Cell Killing and Topoisomerase Activity(Acg Publications, 2012) Sarikaya, Buket Bozkurt; Zencir, Sevil; Somer, Nehir Unver; Kaya, Gulen Irem; Onur, Mustafa Ali; Bastida, Jaume; Berenyi, Agnes; Zupko, Istvan; Topcu, ZekiIn this study, narciprimine and arolycoricidine were isolated from G. rizehensis Stern (Amaryllidaceae). The structures of the alkaloids were elucidated by spectroscopic methods (1D NMR, EI-MS). Due to the previous reports on anti-cancer activity of this group of alkaloids, we investigated their effects on DNA topoisomerase reactions, which are known as the cellular targets of a number of chemotherapeutical drugs. The results revealed that arolycoricidine and narciprimine were effective in both type I and type II DNA topoisomerase reactions in a dose-dependent manner. Topoisomerase-interfering ability of these alkaloids partially correlated with cytostaticity assays, using HeLa (cervix adenocarcinoma), MCF7 (breast adenocarcinoma) and A431 (skin epidermoid carcinoma) cells. Our results are discussed in relation to the potential significance of these alkaloids in the course of drug-development studies.Öğe Effects of Secondary Metabolites from the Fungus Septofusidium berolinense on DNA Cleavage Mediated by Human Topoisomerase II alpha(Amer Chemical Soc, 2016) Vann, Kendra R.; Ekiz, Guener; Zencir, Sevil; Bedir, Erdal; Topcu, Zeki; Osheroff, NeilTwo metabolites from the ascomycete fungus Septofusidium berolinense were recently identified as having antineoplastic activity [Ekiz et al. (2015) J. Antibiot., DOI: 10.1038/ja.2015.84]. However, the basis for this activity is not known. One of the compounds [3,6-dihydroxy-2-propylbenzaldehyde (GE-1)] is a hydroquinone, and the other [2-hydroxymethyl-3-propylcyclohexa-2,5-diene-1,4-dione (GE-2)] is a quinone. Because some hydroquinones and quinones act as topoisomerase II poisons, the effects of GE-1 and GE-2 on DNA cleavage mediated by human topoisomerase IIa were assessed. GE-2 enhanced DNA cleavage similar to 4-fold and induced scission with a site specificity similar to that of the anticancer drug etoposide. Similar to other quinone-based topoisomerase II poisons, GE-2 displayed several hallmark characteristics of covalent topoisomerase II poisons, including (1) the inability to poison a topoisomerase IIa construct that lacks the N-terminal domain, (2) the inhibition of DNA cleavage when the compound was incubated with the enzyme prior to the addition of plasmid, and (3) the loss of poisoning activity in the presence of a reducing agent. In contrast to GE-2, GE-1 did not enhance DNA cleavage mediated by topoisomerase IIa except at very high concentrations. However, the activity and potency of the metabolite were dramatically enhanced under oxidizing conditions. These results suggest that topoisomerase IIa may play a role in mediating the cytotoxic effects of these fungal metabolites.Öğe Experimental Ischemia/Reperfusion Model in Relation to Apototic Cell Death(Federation Amer Soc Exp Biol, 2013) Emre, Mustafa; Demirkol, Serhat; Dora, Devrim D.; Unlukurt, Isa; Topcu, Zeki; Ozsarlak-Sozer, GonenÖğe EXPRESSION OF CYTOCHROME P450-2A6,-3A5 AND-4B1 IN PROSTATE TISSUE(Taylor & Francis Inc, 2007) Zencir, Sevil; Alptekin, Davut; Celiktas, Medih; Colak, Deniz; Luleyap, Umit H.; Topcu, ZekiÖğe Flavonoids in Helichrysum pamphylicum inhibit mammalian type I DNA topoisomerase(Verlag Z Naturforsch, 2008) Topcu, Zeki; Ozturk, Bintug; Kucukoglu, Ozlem; Kilinc, EmrahDNA topoisomerases are important targets for cancer chemotherapy. We investigated the effects of a methanolic extract of Helichrysum pamphylicum on mammalian DNA topoisomerase I via in vitro plasmid supercoil relaxation assays. The extracts manifested a considerable inhibition of the enzyme's activity in a dose-dependent manner. We also performed a HPLC analysis to identify the flavonoid content of the H. pamphylicum extract and tested the identified flavonoids; luteolin, luteolin-4-glucoside, naringenin, helichrysinA and isoquercitrin, on DNA topoisomerase I activity. The measurement of the total antioxidant capacity of the flavonoid standards suggested that the topoisomerase inhibition might be correlated with the antioxidant capacity of the plant.Öğe Glutaminase interacting protein interacts with brain-specific angiogenesis inhibitor 2: a possible link to angiogenesis and cellular signaling(Informa Healthcare, 2011) Zencir, Sevil; Dobson, Melanie; Mohanty, Smita; Topcu, ZekiÖğe Gossypol Interferes with Both Type I and Type II Topoisomerase Activities Without Generating Strand Breaks(Humana Press Inc, 2013) Senarisoy, Muge; Canturk, Pakize; Zencir, Sevil; Baran, Yusuf; Topcu, ZekiA considerable number of agents with chemotherapeutic potentials reported over the past years were shown to interfere with the reactions of DNA topoisomerases, the essential enzymes that regulate conformational changes in DNA topology. Gossypol, a naturally occurring bioactive phytochemical is a chemopreventive agent against various types of cancer cell growth with a reported activity on mammalian topoisomerase II. The compounds targeting topoisomerases vary in their mode of action; class I compounds act by stabilizing covalent topoisomerase-DNA complexes resulting in DNA strand breaks while class II compounds interfere with the catalytic function of topoisomerases without generating strand breaks. In this study, we report Gossypol as the interfering agent with type I topoisomerases as well. We also carried out an extensive set of assays to analyze the type of interference manifested by Gossypol on DNA topoisomerases. Our results strongly suggest that Gossypol is a potential class II inhibitor as it blocked DNA topoisomerase reactions with no consequently formed strand breaks.Öğe Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein(Academic Press Inc Elsevier Science, 2011) Zencir, Sevil; Ovee, Mohiuddin; Dobson, Melanie J.; Banerjee, Monimoy; Topcu, Zeki; Mohanty, SmitaThe vast majority of physiological processes in living cells are mediated by protein-protein interactions often specified by particular protein sequence motifs. PDZ domains, composed of 80-100 amino acid residues, are an important class of interaction motif. Among the PDZ-containing proteins, glutaminase interacting protein (GIP), also known as Tax Interacting Protein TIP-I, is unique in being composed almost exclusively of a single PDZ domain. GIP has important roles in cellular signaling, protein scaffolding and modulation of tumor growth and interacts with a number of physiological partner proteins, including Glutaminase L, beta-Catenin, FAS, HTLV-1 Tax, HPV16 E6, Rhotekin and Kit 2.3. To identify the network of proteins that interact with GIP, a human fetal brain cDNA library was screened using a yeast two-hybrid assay with GIP as bait. We identified brain-specific angiogenesis inhibitor 2 (BAI2), a member of the adhesion-G protein-coupled receptors (GPCRs), as a new partner of GIP. BAI2 is expressed primarily in neurons, further expanding GIP cellular functions. The interaction between GIP and the carboxy-terminus of BAI2 was characterized using fluorescence, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy assays. These biophysical analyses support the interaction identified in the yeast two-hybrid assay. This is the first study reporting BAI2 as an interaction partner of GIP. (C) 2011 Elsevier Inc. All rights reserved.Öğe Identification of transcriptional and phosphatase regulators as interaction partners of human ADA3, a component of histone acetyltransferase complexes(Portland Press Ltd, 2013) Zencir, Sevil; Sike, Adam; Dobson, Melanie J.; Ayaydin, Ferhan; Boros, Imre; Topcu, ZekiADA (alteration/deficiency in activation) 3 is a conserved component of several transcriptional adaptor and HAT (histone acetyltransferase) complexes that regulate RNA polymerase II-mediated gene expression. Within the HAT complexes ADA3 is associated with ADA2 and the HAT GCN5 (general control non-repressed 5). ADA3 plays roles in diverse cellular processes and also in malignancies by modulating GCN5 catalytic activity and/or by interactions with other regulators. To gain a better understanding of ADA3 function, we used a yeast two-hybrid approach to screen a human fetal cDNA library for proteins that interacted with hADA3 (human ADA3). We identified three novel hADA3-interacting partners, a transcriptional regulator, AATF (apoptosis-antagonizing transcription factor), and regulatory subunits of the PP1 (protein phosphatase 1) and PP2A (protein phosphatase 2A) [PPP1R7 (PP1 regulatory subunit 7) and PPP2R5D (PP2A 56 kDa regulatory subunit 8 isoform) respectively]. Analysis of truncated versions of hADA3 indicated that the C-terminal ADA2-interacting domain was not required for these interactions. Fluorescent microscopy analysis and co-immunoprecipitation provided support for the co-localization and interaction of hADA3 with these proteins in human cells. Expression of the interacting proteins altered expression of an hADA3-regulated reporter gene, suggesting functional consequences for the interactions. The detected interactions of hADA3 might extend the spectrum of mechanisms by which ADA3 can contribute to the regulation of gene expression and shed light on processes mediated by these newly identified ADA3 partners.
