Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Studies Toward the Synthesis of Novel Mdm2 Inhibitor Candidates(Izmir Institute of Technology, 2018) Dilek, Fikrican; Çağır, AliProtein protein interactions are valuable targets to discover novel anticancer agents. One of these is the p53-MDM2 interaction. In one of these interaction MDM2 protein inhibits p53 protein and may cause cancer. New drugs that inhibit this interaction are important for the treatment of cancer. One class of these anticancer agents are morpholinone derivative. In this study, it is aimed to synthesize new morpholinone derivatives. (R)-2-amino-2-(4-chlorophenyl)acetic acid was used as starting material for the synthesis. The first step was a trityl protection of amine with trityl chloride. Trityl protected amino acid was first reduced to N-Trt amino alcohol with LiAlH4 then oxidized to aldehyde by using Dess-Martin periodinane. The resulting aldehyde was reacted with 3-chlorophenylmagnesium bromide. This part of the synthesis was performed successfully. Then addition of methyl fumarate to this Grignard product was studied by a coupling reagents such as HATU. All attempts were failed. Then trityl group was removed by TFA and successfully coupled with methyl fumarate by using HATU. All cyclization reactions in the presence of a base like hydroxide, alkoxide or NaH to form morpholinone skeleton was failed. The cyclization reaction with the potassim carbonate in alcohol was successful and the morpholinone skeleton was formed.Master Thesis In-Vitro Evaluation Cytotoxic Potential of Novel Isoindole Derivatives on Various Cancer Cell Lines(01. Izmir Institute of Technology, 2021) Yemeztaşlıca Yetişkin, Egehan; Gülşah Şanlı MohamedCancer, which is the disease of our age, arises because of a very complex set of mechanisms. Especially with the proliferation of cancer disease and the increase in cancer-related deaths, it has a great impact on the development of drug studies by improving existing treatments or researching new treatment methods. Cantharidine and its analogs are natural anhydrides with an inhibitory effect on protein phosphatases. However, they are not included in cancer therapies due to their toxicity. In recent studies, it has been found that derivatives of cantharidin as isoindole-1,3-dione and its derivatives have anticancer effects. The main purpose of this study to investigate the effects of four different drugs, which are newly synthesized isoindole derivatives for use in cancer treatment, on different cancer cells. The cytotoxic effects of drugs on A549 (human lung adenocarcinoma), HeLa (human cervical carcinoma), PC3 (human prostate carcinoma), MCF-7 (human breast carcinoma), and Caco-2 (human colorectal carcinoma) cell lines were investigated by the MTT assay method, and the optimum incubation time was determined, then IC50 values were calculated. Then, the IC50 concentrations of the drugs were applied at 48 hours, which is the optimum incubation period, and apoptotic stages and cell cycle stages were compared using flow cytometry to understand whether the drugs have a suppressive function in cancer development. Scratch assay was performed to investigate the migration effect of drugs on cells. The results showed that the drugs are suppressive to cancer cells and can be used for therapeutic purposes in the future.Master Thesis Studies Toward the Asymmetric Synthesis of Novel Chiral 1,4-Oxazepan Derivatives(01. Izmir Institute of Technology, 2020) Vural, Ezgi; Çağır, AliPharmacophore design to inhibit the interaction between p53 and MDM2 became a novel approach for cancer therapy. p53, known as the guardian of genome, controls the cell cycle arrest, apoptosis and DNA repair under stress. Nonetheless, when over-expressed, MDM2 causes proliferation in the cell and eventually tumorgenesis. The feedback mechanism between p53 and MDM2 arises from the interaction of p53 through the hydrophobic cleft which consists of Phe19, Trp23 and Leu26 aminoacids in the N-terminal of MDM2. In this study, it was aimed to synthesize a new, chiral 1,4-oxazepan-5-one derivatives by asymmetric synthesis. (R)-2-amino-2-(4-chlorophenyl)acetic acid was used as starting material. Amino group was protected by trityl group then the carboxylic acid part was reduced by LiAlH4 to produce N-trityl-protected amino alcohol. Dess Martin periodinane was used for the oxidation of the alcohol to the aldehyde, then 3-chlorophenylmagnesium bromide was added to the aldehyde by Grignard reaction. Deprotection of N-trityl was performed with TFA then, coupling reactions of produced aminoalcohol with different α,β-unsaturated carboxylic acids were performed by HATU and DIPEA. Despite all of the attempts, cyclization to seven membered 1,4-oxazepan-5-one ring was never achieved.Master Thesis Design and Preparation of Alkali Liposomes for Drug Delivery(Izmir Institute of Technology, 2019) Güven, Hatice; Özdemir, Ekrem; Altun, Zekiye SultanCancer is one of the deadliest diseases among other illnesses as an uncontrolled cell division. Liposomal technology has commonly been used in cancer therapy. Chemotherapeutical drugs, genetic materials, different imaging agents can be carried with liposomes. They are preferred by several important characteristics that selective passive targeting of tumors, increased stability and therapeutic index (reducing toxicity) via encapsulation and increased circulation life times with size adjustments. One of the indicator in cell cycle is intracellular pH. The aim of this study is to produce PEGylated alkali liposomes to provide cellular uptake in cancer cells and prevent cell division by changing of intracellular pH. Combination of liposomal technology and alkaline therapy in cancer cells may lead to the development of therapeutic strategies without using any drug to overcome chemoresistance and cell proliferation. For this purpose, alkali liposomes containing sodium carbonate (Na2CO3) solution were prepared and tested their effects on 4T1 breast cancer cell lines in vitro. The cell viabilities were evaluated using trypan blue and WST-1 methods. Pictures were taken for cancer cells to differentiate live and dead cells under different alkali liposome conditions for 5 days. It was found that cell medium containing alkali liposomes up to 3% didn’t affect cell growth. However, cell medium containing alkali liposomes greater than 7% significantly affected the 4T1 breast cancer cell growth and decreased the cell viability to about 40%. It was concluded that PEGylated alkali liposomes were prepared different concentrations to decrease or stop cell division of 4T1 breast cancer cell lines in vitro.Master Thesis Synthesis of Molecularly Imprinted Polymers as Selective Solid Phase Extraction Sorbents for Anticancer Drugs Prior To Chromatographic Determination(Izmir Institute of Technology, 2018) Özdemir, Anıl; Eroğlu, Ahmet E.In recent years, the number of usage of chemotherapic drugs has considerably increased. It is necessary to develop analytical methods to analyse these compounds for quality control of formulations, quality control of diluted formulations before patient usage and understanding compatibility and stability. In this study, novel analytical methods were developed for mostly used anti cancer drugs, namely 5-fluorouracil (5- FU) and 5-azacytidine (5AC). Firstly, two analytical methodologies using capillary electrophoresis (CE) and liquid chromatography (LC) were developed for the determination of 5-FU and 5AC. The CE analysis was performed in a bare fused-silica capillary with 75 μm i.d. and total length of 50.0 cm with a buffer solution of 10.0 mM borate buffer, pH 11.5. The applied voltage was 20.0 kV. The LC analysis was performed with a YMC 30 column in reversed phase and a mobile phase of water–acetonitrile (90:10) at a flow rate of 0.8 mL/min. In both analyses, detection was by ultraviolet absorption. Also, molecularly imprinted polymers (MIPs) with different formulations (different functional monomers, porogens and monomer:crosslinker ratios) and morphologies (monolith and micro/nanosphericalbeads) were synthesized by using bulk and precipitation polymerization strategies. The adsorption capacity of imprinted polymers were compared to their corresponding non-imprinted polymer. MIP prepared by using bulk polymerization strategy with the formulation of 1:1:20 AA was chosen as selective solid phase extraction (SPE) sorbent due to its sorption capacity prior to determination of HPLC-DAD analysis. Selectivity of this imprinted polymer were examined by using 5-FU and 5AC molecules. To improve method, parameters were tested such as pH shaking time and amount of sorbent. So, optimization parameters of method were determined to be pH 5.0 of solution, 100.0 mg of sorbent, 10.0 mL 100.0 mg/L working solution, 60.0 min. sorption time.Master Thesis Comparison Od Side Effects of Anti-Cancer Drugs in 2d and 3d And, Classical and Cell-On Cultures(Izmir Institute of Technology, 2016) Kankale, Deniz; Pesen Okvur, Devrim; Çağır, AliThe studies that aim to assess the effects of drugs developed against cancer at the cellular level use multiwell plates. However, these classical systems fail to reproduce the in-vivo like microenvironment necessary for realistic assessment. In addition, classical cell culture systems use high amount of materials increasing cost. On the other hand, lab-on-a-chip systems use minimal volumes of reagents and more importantly can mimic the in-vivo microenvironment via spatial and temporal control. Furthermore, it is known that cell response to drugs can be very different in 2D and 3D cell culture setups. Doxorubicin is a widely used anticancer drug. Here, doxorubicin uptake by highly metastatic human breast cancer cell line MDA-MB-231 and normal mammary epithelial cell line MCF10A were investigated using 2D and 3D, classical and cell-on-a-chip cultures. Drug uptake at 24, 48 and 72 hours various concentrations of the drug determined by measuring signal intensities from fluorescence microscopy images of cells. For cell viability assay, cells were stained with dapi and two cell lines were compared in systems. According to results, it was observed that 3D cell culture environment in chip provides more in-vivo like environment with less reagent consumption and cell viability is not correlated only with drug uptake.