Person: DAĞ, AYDAN
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Publication Metadata only Targeting cancerous cell lines with glycopolymer micelles(2014-08-10) Dag, AYDAN; BABIUCH, Krzysztof; STENZEL, Martina; DAĞ, AYDANPublication Metadata only Synthesis, anticholinesterase activity and molecular modeling study of novel carbamate-substituted thymol/carvacrol derivatives(2017-02-15) KURT, Belma Zengin; Gazioglu, IŞIL; Dag, AYDAN; Salmas, Ramin Ekhteiari; Kayik, Gulru; Durdagi, Serdar; Sonmez, Fatih; ZENGİN KURT, BELMA; GAZİOĞLU, IŞIL; DAĞ, AYDANNew thymol and carvacrol derivatives with the carbamate moiety were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. 5-isopropyl-2-methylphenyl(3-fluorophenyl)carbamate (29) was found to be the most potent AChE inhibitor with IC50 values of 2.22 mu M, and 5-isopropyl-2-methylphenyl (4-fluorophenyl)carbamate (30) exhibited the strongest inhibition against BuChE with IC50 value of 0.02 mu M. Additionally, the result of H4IIE hepatoma cell toxicity assay for compounds 18, 20, 29, 30 and 35 showed negligible cell death at 0.07-10 mu M. Moreover in order to better understand the inhibitory profiles of these molecules, molecular modeling studies were applied. Binding poses of studied compounds at the binding pockets of AChE and BuChE targets were determined. Predicted binding energies of these compounds as well as structural and dynamical profiles of molecules at the target sites were estimated using induced fit docking (IFD) algorithms and post-processing molecular dynamics (MD) simulations methods (i.e., Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches). (C) 2016 Elsevier Ltd. All rights reserved.Publication Open Access Design, synthesis and docking study of novel coumarin ligands as potential selective acetylcholinesterase inhibitors(2017-01-01) Sonmez, Fatih; KURT, Belma Zengin; Gazioglu, IŞIL; BASILE, Livia; Dag, AYDAN; CAPPELLO, Valentina; GINEX, Tiziana; Kucukislamoglu, Mustafa; GUCCIONE, Salvatore; ZENGİN KURT, BELMA; GAZİOĞLU, IŞIL; DAĞ, AYDANNew coumaryl-thiazole derivatives with the acetamide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and in vitro tested as acetylcholinesterase (AChE) inhibitors. 2-(diethylamino)-N-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)acetamide (6c, IC50 value of 43 nM) was the best AChE inhibitor with a selectivity index of 4151.16 over BuChE. Kinetic study of AChE inhibition revealed that 6c was a mixed-type inhibitor. Moreover, the result of H4IIE hepatoma cell toxicity assay for 6c showed negligible cell death. Molecular docking studies were also carried out to clarify the inhibition mode of the more active compounds. Best pose of compound 6c is positioned into the active site with the coumarin ring wedged between the residues of the CAS and catalytic triad of AChE. In addition, the coumarin ring is anchored into the gorge of the enzyme by H-bond with Tyr130.Publication Metadata only Polymer-Albumin Conjugate for the Facilitated Delivery of Macromolecular Platinum Drugs(2015-05-01) Dag, AYDAN; JIANG, Yanyan; ABD KARIM, Khairil Juhanni; HART-SMITH, Gene; SCARANO, Wei; STENZEL, Martina H.; DAĞ, AYDANThe delivery of macromolecular platinum drugs into cancerous cells is enhanced by conjugating the polymer to albumin. The monomers N-(2-hydroxypropyl)methacrylamide (HPMA) and Boc protected 1,3-diaminopropan-2-yl acrylate (Ac-DAP-Boc) are copolymerized in the presence of a furan protected maleimide functionalized reversible addition-fragmentation chain transfer (RAFT) agent. The resulting polymer with a composition of P(HPMA(14)-co-(Ac-DAP-Boc)(9)) and a molecular weight of M-n = 7600 g mol(-1) (D = 1.24) is used as a macromolecular ligand for the conjugation to the platinum drug. Thermogravimetric analysis reveals full conjugation. After deprotection of the maleimide functionality of the polymer, the reactive polymer is conjugated to albumin using the Cys34 functionality. The conjugation is monitored using size exclusion chromatography, MALDI-TOF (matrix assisted laser desorption ionization time-of-flight), and SDS Page (sodium dodecyl sulphate polyacrylamide gel electrophoresis). The polymer-albumin conjugates self-assemble in water into nanoparticles of sizes of around 80 nm thanks to the hydrophobic nature of the platinum drugs. The albumin coated nanoparticles are readily taken up by ovarian cancer cell lines and they show superior toxicity compared to a control sample without protein coating.Publication Metadata only Synthesis and characterization of novel tetra terminal alkynyl-substituted phthalocyanines and their star polymers via click reaction(2013-08-01) Dincer, Hatice; Mert, Humeyra; Sen, Betul Nur; Dag, AYDAN; Bayraktar, Sinem; DAĞ, AYDANFor the first time, symmetrically tetra terminal alkynyl-substituted phthalocyanines (Pcs) were functionalized with polymers, that is, via 1,3-dipolar cycloaddition reaction. For this purpose, 4-pent-4-ynyloxyphthalonitrile (3) was prepared by the nucleophilic displacement reaction of 4-nitrophthalonitrile (1) and 4-pentyne-1-ol (2). The syntheses of the target 2,9(10),16(17),23(24)-tetra terminal alkynyl-substituted phthalocyanines (4-6) were achieved with reasonable yields by a direct cyclotetramerization reaction in the presence of zinc acetate, cobalt acetate, and/or DBU in pentanol without protection/deprotection. Successful -click- reactions between well defined azido-terminated polystyrene (PS-N-3) (7) or poly(tertbutyl acrylate) (PtBA-N-3) (8) and alkynyl-terminated phthalocyanines (4, 5) yielded four arm star polymers. The precursors and the target star polymers were characterized comprehensively by H-1 NMR, C-13 NMR, FT-IR, UV-Vis, GPC and elemental analysis. (C) 2013 Elsevier Ltd. All rights reserved.Publication Open Access Assessment of in vitro cytotoxic and genotoxic activities of some trimethoprim conjugates(2018-06-01) Bayulken, Devrim Guzel; Bostancioglu, R. Beklem; Koparal, A. Tansu; Tuylu, Berrin Ayaz; Dag, AYDAN; Benkli, KADRİYE; DAĞ, AYDAN; BENKLİ, KADRIYETrimethoprim, a commonly used antibacterial agent, is widely applied in the treatment of variety of infections in human. A few studies have demonstrated an extensive exposure of man to antibiotics, but there is still a lack of data for cytotoxic effects including nephrotoxicity, gastrointestinal toxicity, hematotoxicity, neurotoxicity and ototoxicity. The main purpose behind this study was to determine cytotoxic and genotoxic activities of trimethoprim (1), trimethoprim with maleic acid (2) and trimethoprim in conjugation with oxalic acid dihydrate (3). The cytotoxic effects of these three conjugates were elucidated by employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoium bromide (MTT) assay using embryonic rat fibroblast-like cell line (F2408) and H-ras oncogene activated embryonic rat fibroblast-like cancer cell line (5RP7). Additionally, determination of genotoxic activity of these three compounds were studied by using cytokinesis blocked micronucleus assay (CBMN) in human lymphocytes. The results demonstrated that trimethoprim alone and its combination with other compounds are able to induce both cytotoxic and genotoxic damage on cultured cells (F2408, 5RP7, human lymphocytes).Publication Metadata only Fructose-coated nanoparticles: a promising drug nanocarrier for triple-negative breast cancer therapy(2014-01-01) ZHAO, Jiacheng; BABIUCH, Krzysztof; Lu, Hongxu; Dag, AYDAN; GOTTSCHALDT, Michael; STENZEL, Martina H.; DAĞ, AYDANFructose transporter GLUT5 is overexpressed in breast cancer cell lines, but not in healthy tissue. Micelles based on fructose, which were found to be low fouling, showed a high uptake by breast cancer cells (MCF-7 and MDA-MB-231 cells), but only negligible uptake by macrophages.Publication Metadata only Carbohydrate-Specific Uptake of Fucosylated Polymeric Micelles by Different Cancer Cell Lines(2015-07-01) BABIUCH, Krzysztof; Dag, AYDAN; ZHAO, Jiacheng; Lu, Hongxu; STENZEL, Martina H.; DAĞ, AYDANInspired by upregulated levels of fucosylated proteins on the surfaces of multiple types of cancer cells, micelles carrying beta-L-fucose and beta-D-glucose were prepared. A range of block copolymers were synthesized by reacting a mixture of 2-azidoethyl beta-L-fucopyranoside (FucEtN(3)) and 2-azideoethyl beta-D-glucopyranoside (GlcEtN(3)) with poly(propargyl methacrylate)-block-poly(n-butyl acrylate) (PPMA-b-PBA) using copper-catalyzed azide-alkyne cycloaddition (CuAAC). Five block copolymers were obtained ranging from 100 mol % fucose to 100% glucose functionalization. The resulting micelles had hydrodynamic diameters of around 30 nm. In this work, we show that fucosylated micelles reveal an increased uptake by pancreatic, lung, and ovarian carcinoma cell lines, whereas the uptake by the healthy cell lines (CHO) is negligible. This finding suggests that these micelles can be used for targeted drug delivery toward cancer cells.Publication Metadata only Dual-Responsive pH and Temperature Sensitive Nanoparticles Based on Methacrylic Acid and Di(ethylene glycol) Methyl Ether Methacrylate for the Triggered Release of Drugs(2015-08-01) KHINE, Yee Yee; JIANG, Yanyan; Dag, AYDAN; Lu, Hongxu; STENZEL, Martina H.; DAĞ, AYDANA series of thermo-and pH-responsive poly(methyl methacrylate)-block-poly[methacrylic acid-co-di(ethylene glycol) methyl ether methacrylate] PMMA-b-P[MAA-co-DEGMA] block copolymers were synthesized by RAFT polymerization and self-assembled into micelles. The molar ratio of MAA was altered from 0-12% in order to modulate the lower critical solution temperature (LCST) of PDEGMA. The release of the drug albendazole from the micelle was strongly dependent on the temperature and the LCST value of the polymer. Systems below the LCST released the drug slowly while increasing the temperature above the LCST or decreasing the pH value to 5 resulted in the burst-like release of the drug. ABZ delivered in this pH-responsive drug carrier had a higher toxicity than the free drug or the drug delivered in a non-responsive drug carrier.Publication Metadata only Light-responsive azobenzene-based glycopolymer micelles for targeted drug delivery to melanoma cells(2015-08-01) PEARSON, Samuel; VITUCCI, Dylan; KHINE, Yee Yee; Dag, AYDAN; Lu, Hongxu; SAVE, Maud; BILLON, Laurent; STENZEL, Martina H.; DAĞ, AYDANLight-responsive glycopolymer micelles were produced by the self-assembly of amphiphilic block copolymers containing azobenzene and beta-galactose units. These well-defined block copolymers were synthesised firstly by the RAFT polymerisation of an azobenzene methacrylate monomer (AzoMA) to produce two short azobenzene macroRAFT agents containing 7 and 15 monomer units. Chain extension with a second block of similar to 150 or similar to 250 sugar units comprising of a protected beta-galactose monomer (beta-AcGalEtMA) generated four block copolymers, which were converted to amphiphilic structures by deprotection of the acetyl groups on the sugar units. Micelles with well-defined sizes of 26-50 nm were produced by self-assembly in water. The azobenzene units isomerised very rapidly to their more polar cis isomers under UV irradiation, reaching the photostationary state within 2 min, with reversion to the trans state taking several hours in the dark. This transition to the more polar cis state is an important criteria for aiding expulsion of a hydrophobic payload. In cell studies, unloaded micelles showed low cytotoxicity, and micelles loaded with the model hydrophobic compound Nile red demonstrated high cellular uptake in human melanoma A375 cells, demonstrating their suitability as a potential drug delivery system for melanoma. (C) 2015 Elsevier Ltd. 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