Master Degree / Yüksek Lisans Tezleri

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  • Master Thesis
    Investigation of the Effect of 4'-alkylıklavuzon Derivatives on Nucleotide Synthesis and Nucleocytoplasmic Transport
    (Izmir Institute of Technology, 2016) Köksal, Mustafa; Köksal, Mustafa; Çağır, Ali; Çağır, Ali; Köksal, Mustafa; 04.03. Department of Molecular Biology and Genetics; 04.01. Department of Chemistry; 04. Faculty of Science; 01. Izmir Institute of Technology
    In anti-cancer agent development studies one of the most significant issue is to get an agent that specifically targets cancer cells without any effects on healthy cells. Goniothalamin, that is a styryl lactone isolated from Goniothalamus plant species, is an anti-cancer agent that has selective anti-proliferative activity on cancer cell lines. Klavuzon and derivatives, which can be thought as analogs of goniothalamin, are more cytotoxic in cancer cells compared to goniothalamin. Previous structure activity relationship studies implies that α,β-unsaturated δ-lactone moiety is the source of the biological activity. Since it behaves as Michael acceptor, in this thesis possible irreversible inhibitions of two separate intracellular targets are investigated. In the first part, thymineless death caused by possible thymidylate synthase inhibition has been studied. Anti-proliferative effect of 4’-methylklavuzon in HuH-7 cancer cell line was tested by using MTT. Viability of klavuzon treated cells did not changed significantly in the absence and presence of varying concentration of additional thymidine supplement, and it is concluded that thymineless death is not a crucial mechanism for klavuzon derivatives. In the second part, 4’-methylklavuzon and its derivatives were tested on HeLa cell line to investigate inhibitory effect on the nucleocytoplasmic transport. Immunocytochemistry was used to demonstrate nucleocytoplasmic localization of Riok2 protein which is transferred from nuclei to cytoplasm by CRM1 nuclear export protein. Successfully, all tested klavuzon derivatives inhibit CRM1 nuclear export protein. Potency of the inhibition depends on the size of the alkyl substituent at 4’- position of klavuzon.
  • Master Thesis
    Investigation of the Anti-Cancer Properties of Novel 4'-alkyl Substituated Klavuzon Derivatives on Pancreatic Cancer Cell Line
    (Izmir Institute of Technology, 2015) Şen, Ayhan; Çağır, Ali; Çağır, Ali; 04.01. Department of Chemistry; 04. Faculty of Science; 01. Izmir Institute of Technology
    In anti-cancer agent studies one of the important issue is to discover an agent that target specifically cancer cells with no or minimal effects on normal cells. (R)-goniothalamin, which is a styryl lactone isolated from plants, is an anti-cancer agent that is cytotoxic to cancer cell lines with no or minimal effect on normal cells. Also klavuzon molecule, the 1-naphthyl substituted 5,6-dihydro-2H-pyran-2-one derivative, was tested on cancer cell lines and showed higher cytotoxicity. In the first part of this study anti-proliferative effect of novel 4’-alkyl substituted klavuzon derivatives were tested on MIA PaCa-2 cancer cell line and normal Human Pancreatic Duct Epithelial Cell (HPDEC) line by using MTT, and it is found that cytotoxic activity of the compounds depends on the size of the substituent at position 4 in 1-naphthyl part. While two of them, methyl and ethyl substituted, showed high cytotoxicity to MIA PaCa-2 that IC50 values in nano-molar levels. Next studies were continued with 4’-methylklavuzon derivative. In the second part, the apoptotic effect and cell cycle analysis of 4’-methylklavuzon was studied. Especially at the 10 μM concentration there was increment in both early and late apoptosis. Cell cycle analysis showed that increasing the concentration of molecule caused cell cycle arrest in S and G2 phases. The next part was testing the inhibitory effect of 4’-methylklavuzon on human topoisomerase I enzyme. This enzyme was chosen as one potential target, because 4’-methylklavuzon caused S and G2 phase arrest. Topo I is an actively working enzyme during S phase and inhibition of its activity causes DNA fragmentation and apoptosis. The results showed that there was time dependent inhibition of Topo I enzyme in vitro. The last part of the study was to show DNA fragmentation at cellular level by COMET assay, also known as Single Cell Gel Electrophoresis. After Topo I assay has showed the Topo I inhibition activity of 4’-methylklavuzon, COMET assay was performed. Especially at the 5 μM concentration comets were formed and tail moments were parallel with positive control.