Browsing by Subject "Anticancer"
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Item Open Access Cytotoxic activities of some benzothiazole-piperazine derivatives(Taylor and Francis Ltd, 2015) Gurdal, E.E.; Durmaz I.; Cetin-Atalay, R.; Yarim, M.Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Compound 1d is highly cytotoxic against all tested cancer cell lines. Further investigation of compound 1d by Hoechst Staining and Fluorescence-Activated Cell Sorting Analysis (FACS) revealed that this compound causes apoptosis by cell cycle arrest at subG1 phase. © 2014 Informa UK Ltd. All rights reserved.Item Open Access Discovery of novel agents for liver cancer therapeutics and characterization of their bioactivities on cellular pathways(Bilkent University, 2015-12) Durmaz, İremHepatocellular carcinoma is the second deadliest and fifth most common cancer type worldwide. Due to the limited therapy options, it is crucial to develop novel targeted therapeutic agents that provide better prognosis and enhance life quality of patients. The specific aim of this thesis was to identify and characterize novel compounds with anticancer properties in liver cancer. Three groups of molecules were investigated. First group were cardiac glycosides extracted and purified from Digitalis Ferruginea. Extensive analysis Glycoside Lanatoside C revealed that these molecules induced ROS accumulation in liver cancer cells with differential downstream targets in mesenchymal-like PTENdeficient drug-resistant Mahlavu and epithelial-like PTEN-adequate drug-sensitive Huh7 liver cancer cells. Xenograft models on nude mice also confirmed the anticancer activities of Lanatoside C in vivo with decreased tumor volume and weight. The second group of compounds were novel molecules that contains triazolothiadiazine and triazolothiadiazole scaffold, derived from known NSAIDs (ibuprofen, naproxen and flurbiprofen). Results indicated that SubG1/G1 cell cycle arrest is induced in treated cells. In addition, extensive molecular analysis disclosed oxidative stress induction and COX activity inhibition leading to ASK1 activation and Akt inhibition. The levels of downstream elements GSK3β, β-catenin and CyclinD1 were also altered. Apoptosis was characterized as the cell death mechanism that is triggered by these molecules in liver cancer cells. Novel nucleobase/nucleoside analogues were the third group of molecules explored in this study. 24 of 127 investigated compounds showed significant cytotoxicity during initial screening. 6 molecules were selected for further molecular analysis upon real-time cytotoxicity assay. It was observed that the molecules induced SubG1/G1 cell cycle arrest through Src pathway inhibition. CyclinE-cdk2 complex formation was prevented then the inhibition of Rb leading to a decrease in cell growth and proliferation and induction of apoptosis in liver cancer cells. This thesis disclosed the mode of action of three groups molecules, glycosides are pure examples of drug repurposing. NSAID represent the modified small molecule compounds for novel targets and finally nucleobase analogs are novel compounds as anti metabolites.Item Open Access Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies(Taylor and Francis, 2014) Akı-Yalçın, E.; Ertan-Bolelli, T.; Taşkın-Tok, T.; Öztürk, Ö.; Ataei, S.; Özen, Çiğdem; Yıldız, I.; Yalçın, I.There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.Item Open Access A series of 2,4(1H,3H)-quinazolinedione derivatives: synthesis and biological evaluation as potential anticancer agents(Bentham Science Publishers, 2016) Akgün, H.; Us-Yılmaz, D.; Çetin-Atalay, Rengül; Gözen, DamlaA series of 6,7-disubstituted-3-{2-[4-(substituted)piperazin-1-yl]-2-oxoethyl}quinazoline- 2,4(1H,3H)-dione derivatives (7-34) were synthesized and their structures were elucidated on the basis of analytical and spectral (UV, IR, 1H-NMR, 13C-NMR and MS) data. These synthesized compounds were evaluated for their in vitro cytotoxicities against a panel of three human cancer cell lines. According to the cytotoxicity screening results, 3-{2-[4-(4-chlorobenzyl)piperazin-1-yl]-2-oxoethyl} quinazoline-2,4(1H,3H)-dione (7) presented the highest activity against HUH-7, MCF-7 and HCT-116 cell line with the IC50 values of 2.5, 6.8 and 4.9 µM, respectively.Item Open Access Synthesis and anticancer activity evaluation of some benzothiazole-piperazine derivatives(Bentham Science Publishers B.V., 2015) Gurdal, E.E.; Buclulgan, E.; Durmaz I.; Cetin-Atalay, R.; Yarim, M.Synthesis, characterization and cytotoxic activities of ten benzothiazole-piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Aroyl substituted compounds 1h and 1j were found to be the most active derivatives. In addition, further investigation of compounds 1h and 1j by Hoechst staining and FACS revealed that these compounds cause apoptosis by cell cycle arrest at subG1 phase. © 2015 Bentham Science Publishers.Item Open Access Synthesis and cytotoxic activity of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1 H-indole derivatives(Thieme, 2012) Koksal, M.; Yarim, M.; Durmaz, I.; Cetin Atalay, R.A series of novel 3-methyl-1-[(4-substitutedpiperazin-1-yl)methyl]-1H- indoles (3a-l) were synthesized and their cytotoxicities were analyzed against 3 different human cell lines, including liver (HUH7), breast (MCF7) and colon (HCT116). The Mannich reaction of 3-methylindole (1) with 4- substitutedpiperazines (2) and formaldehyde resulted to the 3-methyl-1-[(4- substitutedpiperazin-1-yl)methyl]-1H-indoles (3a-l) in 38-69% yields. The investigation of anticancer screening revealed that the tested compounds showed comparable activity to the reference drug 5-fluorouracil and compounds 3g, 3h, 3i and 3k, had lower 50% inhibition (IC 50) concentration than reference drug. Moreover, the cytotoxic effect of the most potent compound 3h on HUH7 and MCF7 cells through apoptosis was visualized by Hoechst staining and compared with paclitaxel, which is a mitotic inhibitor acting on microtubules. The morphological features of apoptosis were observed as condensed and fragmented nuclei that are similar to paclitaxel. © Georg Thieme Verlag KG Stuttgart.New York.