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 Investigation of Anticancer Properties of Novel Mdm2 Inhibitors(Izmir Institute of Technology, 2021) Özdemir, Sefayi Merve; Çağır, AliCancer is one major disease causing death worldwide. Current cancer treatments are not %100 effective to cure for patients, yet. Thereby, the synthesis and discovery of new therapeutics have been important to improve the survival period of the cancer patients. There are many strategies for synthesis of cancer therapeutics. One of the most important strategy for cancer treatment is the reactivation of p53. MDM2 is a negative regulator of p53 in cell, because it causes the inactivation of p53. In this thesis, the anticancer and MDM2 inhibitory properties of ezetimibe, desfluoro ezetimibe and intermediates during ezetimibe synthesis (named as SM2-9) and a side product from the synthesis of benidipine (named as SM1) on prostate cancer (LnCAP, wild-type p53), breast cancer (MCF7, wild type p53) and uterus cancer (HeLa, wild type nonfunctional p53) cells were investigated. For this purpose, the cytotoxic, cytostatic and apoptotic properties of these compounds were determined. Compounds SM2, SM3, SM4 and SM6 demonstrated cytotoxic effects, whereas compounds SM5, SM8 and SM9 had cytostatic effects on three cells. Compound SM7 had no effect on these cells, up to 100 μM concentration. Compounds SM1 had cytostatic effect on MCF7 cells, but it showed no activity on other cells. Compounds SM8 and SM9 had strong cytostatic activity. Thus, the apoptotic properties of these compounds were examined by caspases 3/7 activation and Annexin-V FITC assays. Besides, MDM2 inhibitor profiles of these compounds were investigated by fluorescence polarization assay. This study provides novel and potential molecules for drug discovery in cancer treatmentMaster Thesis The Evaluation of Antiproliferative and Structural Effects of Statins on Non-Small Lung Cancer Cell Line A549(Izmir Institute of Technology, 2019) Aksoy, Hatice Nurdan; Ceylan, Çağatay; Çağır, AliStatins are commonly prescribed anti-lipidemic and anti-cholesterol class of drugs. In addition to their major role, they have been found to have anti-cancer effects on in vitro, animal and clinical studies. The aim of this study was to investigate the structural effects of 6 different statins (rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin and atorvastatin) on A549 cells by a spectroscopic method. MTT viability tests were carried out to detect the half maximal inhibitory concentrations (IC50) of each statin on A549 cells. The IC50 values were 50 μM for simvastatin, 150 μM for atorvastatin and pravastatin, and 170 μM for fluvastatin, 200 μM for rosuvastatin and lovastatin on A549 cells. The cells were treated with IC5, IC10 and IC50 values of each statins concentration and their whole cell extracts and lipid extracts were compared using FTIR spectroscopy which is one of the most useful techniques to evaluate the structural changes at the macromolecular functional group level. The results indicated that different statins have different prominent effects on A549 cells. All the statins studied caused observable conformational changes on DNA and proteome of A549 cells. Whereas atorvastatin led to lipidation, lovastatin and pravastatin indicated enormous lipid-lowering properties. Based on the cell lipid extracts it was found that hydrocarbon chain length, unsaturation index, phospholipid containing lipids and carbonyl index showed increasing except for rosuvastatin-treated A549 cells. This study indicated that statins caused significant structural and compositional changes on A549 cells based on a spectroscopic evaluation.Master Thesis Lab-on-a-chip devices for drug screening(Izmir Institute of Technology, 2019) Gökçe, Begüm; Pesen Okvur, Devrim; Çağır, AliBreast cancer is one of the cancers with the highest incidence and mortality rates in women in Turkey as well as in the world. Tumor micro environment comprises of cancer and normal cells, extracellular matrix, soluble biological and chemical factors. Research has shown that cell shape, adhesion, migration, response to growth factors and drugs are different in 2D and 3D culture. Today, only 8 out of 100 anti-cancer clinical trial gives effective results. 3D cell culture systems have shown to be a necessary step between in vitro, in vivo and clinical studies. Therefore, it is necessary to better understand the interactions of cancer cells with their micro environment, for which new cell culture setups are required. The most apparent disadvantage of widely used 3D cell culture setups is the lack of stromal cells. The systems to be developed should both provide a 3D environment and comprise multiple cell types. The drug screen in 3D tri-culture method with a lab-on-a-chip device, that will be developed in this study will be able to answer these needs. Cell lines that represent different breast cancer types alone or together with stromal cells were cultured in 3D in the to be developed lab-on-a-chip; by determining the effects of drugs with different targets on the viability and distribution of cells, a drug screening method is developed.Master Thesis Fungal Biotransformation of Novel 20(27)- Octanor Cycloastragenol and Biological Activities of the Purified Metabolites(Izmir Institute of Technology, 2019) Duman, Seda; Bedir, Erdal; Çağır, AliBiotransformation is the chemical modifications performed by enzymes or living organisms. The difficulty and high cost of enzyme isolation and purification makes it more advantageous to use whole cell systems as biocatalysts. Microbial biocatalysts are particularly interesting in the modification of complex molecules such as steroids and triterpenoids, which can catalyze stereo- and regio- selective reactions that are difficult or impossible to perform with chemical reactions. Specially, ability of endophytic microorganisms to produce specific enzymes for adaptation to their environment by tolerating toxic defense metabolites, makes them interesting for biotransformation studies. Telomeres are nucleotide structures located at the end of chromatids shortening with each cell division. Telomerase is a reverse transcriptase enzyme, and it helps to replenish telomere ends that are truncated by aging and stress factors. The telomerase activators (TA) with their potentials are suggested encouraging agents for healthy aging, and they are projected to generate a huge market in the future. Cycloastragenol is the only natural product in the sector marketed as a potent telomerase activator. In this study, by using endophytic fungi, the biotransformation studies were performed on 20(27)-octanor cycloastragenol. As a result, 14 biotransformation products, were isolated by chromatographic studies, and the structures of the metabolites were established by spectral methods. Based on the literature survey, 13 compounds turned out to be new for nature. Seven metabolites were screened for telomerase activation. In these screenings, metabolites showed telomerase activation ranging from 5.43 to 12.36 fold at doses ranging from 0.1 to 30 nM compared to the control cells treated with DMSO.Master Thesis Synthesis of Simple 2'-alkoxymethyl Substituted Klavuzon Derivatives(Izmir Institute of Technology, 2017) Çetinkaya, Hakkı; Çağır, Aliα,β-Unsaturated δ-lactones are the members of lactones, which are cyclic esters. They are quite valuable compounds because of their Michael acceptor property at unsaturated carbonyl functional group. It is believed that soft nucleophilic parts of the enzymes react with the β-carbon of lactone and form a covalent bond. If that is occurred at the active site of an enzyme, its activity is inhibited irreversibly. (R)-goniothalamin is a α,β-unsaturated lactone and it was shown that it has a selective cytotoxic activity over cancer cells. It is less cytotoxic in healthy cells. Later, Kasaplar and coworkers synthesized the klavuzon derivatives, which can be considered as the close relatives of goniothalamins. In this study novel derivatives of simple 2’-alkoxymethyl substituted klavuzon derivatives were synthesized. For this purpose, we started with 2-methyl-1-naphtoic acid, which can be transferred to ethyl 2-methyl-1-naphtoate by reacting with iodoethane under basic condition. Next, formed ester reacted with Br2 molecules generated in situ by NaBrO3 and NaHSO3. Then formed ethyl 2-(bromomethyl)-1-naphtoate reacted with various alcohols under basic conditions to form ethyl-2-alkoxymethyl-1-naphtoate. These esters are coverted to the target klavuzon products in five steps that are reduction with LiAlH4, oxidation with PCC, addition of allylmagnesium bromide, acrylate ester formation and ring closing metathesis reactions.Master Thesis Antiproliferative Properties of 2'-alkoxymethyl Substituted Klavuzon Derivatives(Izmir Institute of Technology, 2017) Yıldız, Mehmet Salih; Pesen Okvur, Devrim; Çağır, Ali; Çağır, Ali; Pesen Okvur, DevrimOne of the main objectives of studies on anticancer agents is that the agent is expected to show a high cytotoxic activity on cancer cells and show a less cytotoxic effect on the contrary in healthy cells or never show cytotoxic activity. (R)- goniothalamin, isolated from the Goniothalamus plant, is a styryl lactone and has been found to have a selective antiproliferative property on cancer cells in studies conducted. The Michael acceptor feature in the structure of goniothalamin is thought to be covalently bonded to the nucleophilic side chains of the enzymes and show activity in this way. In previous studies, it has been shown that 1-naphthyl substituted 5,6-dihydro- 2H-pyran-2-one derivatives and 4'-methyl klavuzon derivatives exhibit higher cytotoxic activity on cancer cells than goniothalamin. In this study, antiproliferative properties of newly synthesized 2'-alkoxymethyl substituted klavuzon derivatives have been examined and MIA PaCa-2 pancreatic cancer cell lines and HPDEC pancreatic healthy cell lines were used. MTT cell viability tests were performed at the first step of this study. As a result of this study, it has been observed that the 2'-isobutoxymethylklavuzon derivative has selective cytotoxic activity on the MIA PaCa-2 cell line. It showed activity at lower concentrations than goniothalamin. Cytotoxic activities of the compounds are associated with the size of the R group at position 2’-. Methoxymethyl substituted the worst selective activity among these compounds whereas isobutoxy derivative the best selective one. In the second stage of the study, the inhibition on topoisomerase I enzyme was studied. The 2'-alkoxymethyl klavuzon derivatives were found to have Topo I enzyme inhibition properties depending on concentration and time manner. The study continued with choices methoxy and isobutoxy derivatives and these two compounds caused an arrest at G1 phase and DNA damage. Also, isobutoxy derivative induced apoptosis in the MIA PaCa-2 pancreatic cancer cell lines.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.Master Thesis Investigation of the Effect of 4'-alkylıklavuzon Derivatives on Nucleotide Synthesis and Nucleocytoplasmic Transport(Izmir Institute of Technology, 2016) Kutluer, Meltem; Köksal, Mustafa; Çağır, Ali; Çağır, Ali; Köksal, MustafaIn 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, AliIn 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.