Master Degree / Yüksek Lisans Tezleri
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Master Thesis Synthesis of 1,5-Disubstituted 1,2,3-Triazole Modified Azacoumarins(01. Izmir Institute of Technology, 2022) Çetin, Başak; Çağır, AliCancer is a deadly disease that threatens human health and all life, and it is still a serious problem despite all scientific studies for more than half a century. Pharmacophores are a part of the structure of a drug (or drug candidate) responsible from the biological activity. This thesis is related with the synthesis of novel compounds having two well-known pharmacophore structures, 1,2,3-triazole and 1-azacoumarin. Both structures can be found in the structure of many biologically active molecules. Triazole modified coumarin derivatives are scarce in the literature. In this study, we aimed to improve the synthetic route toward the synthesis of 1- azacoumarin derivative modified by 1,2,3-triazole group at position 4-. Synthesis starts with the conversion of methyl 4-chloroanthranilate to the corresponding 4-OH azacoumarin. Then it is transferred into the 4-OTf group by simply addition of Tf group to OH under basic condition. After Sonogashira reaction and removal of TMS group 4- alkynyl-1-azacoumarin was produced. At this point, conversion of alkyne into 1,5- disubstituted 1,2,3-triazole was examined in the presence of Cp2Ni-Xantphos and RuCl(COD)Cp* catalytic systems but all of trials were failed probably due to the presence of ester group close to the reaction site. In further studies, design of the molecule will be reperformed and ester group will be moved over phenyl rings in order to test its biological activity over cancer cell lines.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 Synthesis of 1,2,3-Triazole Substituted Azacoumarin Derivatives as Potential Antiproliferative Compounds(01. Izmir Institute of Technology, 2021) Erdoğmuş, Mustafa; Çağır, AliCancer is one of the deadly diseases that affects millions of people every year and causes death. Although studies toward its treatment are very promising, they are not sufficient. Therefore, the need for new and powerful molecules with less side effects is increasing day by day. 1-Azacoumarin derivatives are molecules whose potential biological activity has just begun to be understood, but not enough research has been done on them. 1,2,3-Triazole structures, on the other hand, are a very important family of molecules in some drugs, whose biological effects have been known for many years. It is known that they have important roles in cancer-preventing mechanisms in various types of cancer. In this study, two different 1,2,3-triazole 1-azacoumarin derivatives were tried to be synthesized. For structure 149, it was aimed to form yinon first and then formation of 1,2,3-triazole was studied but failed. Afterwards, the emphasis was placed on the production of 1-azacoumarin, and then click chemistry experiments were carried out in the presence of copper (I) catalyst. Finally, click chemistry studies were tested in the presence of a nickel catalyst for structure 150. Triazole formation experiments were carried out by click chemistry in the presence of copper catalyst after 1-azacoumarin was obtained.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 Studies Toward the Asymmetric Synthesis of Ester Functionalized Novel 1,4-Oxazepine Derivatives(01. Izmir Institute of Technology, 2021) Bozoğlu, Hülya; Çağır, AliThe MDM2/p53 is one of the most widely studied protein-protein interaction because of being a valuable target for the development of novel anticancer agents. MDM2 protein is the natural inhibitor of p53 protein which act as a tumor suppressor. When MDM2 is overexpressed, damaged DNA is allowed to replicate and therefore cancerous cells can be generated because p53 has lost of its activity. For this reason; maintaining the activity of wild-type p53 through inhibition of MDM2 can stop the proliferation of cancer cells. New drugs that inhibit this interaction are important for the treatment of cancer. The aim of the study is synthesize chiral 1,4-oxazepine-5-one 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 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. Up to this part of the synthesis, reactions were performed successfully. Then trityl group was removed by TFA and amino alcohol was obtained. Then addition of several α,β-unsaturated carbonyls to the deprotected amino alcohol was studied by coupling reagents such as HATU. Afterwards we performed some intramolecular cyclization attempts but all cyclization attempts were failed.Master Thesis Synthesis of Novel Coumarin-1,2,3 Hybrids as Potential Anticancer Agents(01. Izmir Institute of Technology, 2021) Akman, Bora; Çağır, AliCoumarin and triazole derivatives have been extracted from plants, seeds and roots for ages in traditional methods. As the science advances, unknown profits of biologically active compounds have been investigating by researchers in modern laboratories. Extracts of natural sources containing coumarin and triazole derivatives were found to be potential natural medicines. The organic structures of these molecules bear extraordinary biological activities such as inflammatory activity, anti-HIV activity, treatment of cold and rheumatism and anticancer activity. In this study, attemps toward the synthesis of coumarin-triazole hybrids will be presented. At first attempt, starting from 2-amino-5-chlorophenol, coumarin-triazole hybrids were tried to be obtained through ynone intermediates, yet the experiments on acquiring corresponding ynone intermediates were failed. As second approach, 4-iodocoumarin and 4-bromocoumarin derivatives were tried to be synthesized from 4-hydroxycoumarin derivative that was acquired from acetyl salicylic acid, and the attempts were failed again. As an alternative, 4-tosylcoumarin derivative was used as pseudo halogenated coumarin derivative with triazole derivatives that were prepared starting from 4-chlorobenzyl azide. However, the failure was witnessed after all trials. In further trials, obtaining an internal alkyne as Sonogashira product from 4-tosylcoumarin derivative was the first step of another approach to produce desired hybrid structures. Unfortunately, in the second step a click chemistry between Sonogashira product and 4-cholorobenzyl azide was failed to form corresponding hybrid structures. Finally, possible Heck reaction was studied between coumarin derivative and 5-iodo-1,2-disubstituted-1,2,3-triazole derivative, that was also failed to obtain desired coumarin-triazole hybrid.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 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.
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