Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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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 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 Syntheses of Novel 3,6-Dihydro and Klavuzon Derivatives(Izmir Institute of Technology, 2015) Kara, Murat; Çağır, AliThe styryl-lactones are a group of secondary metabolites which have unsaturated lactone moiety in their structures. One of the most important member of this group of compound is goniothalamin. Goniothalamin and its analogs having a common -unsaturated lactone moiety. Investigations on these species have been increased in the last decade because of their interesting biological activities. Present study aims the synthesis of novel 4’-alkyl substituted klavuzon and naphthalen-1-yl substituted 3,6-dihydro-2H-pyran-2-one derivatives. Syntheses were started with the preparation of ethyl 4-(bromomethyl)-1-naphthoate. Copper-catalyzed cross coupling reactions between ethyl 4-bromoethyl-1-naphthoate and Grignard reagents gave alkyl substituted esters. Next, alkylated ester derivatives were converted to alklylated-naphthaldehyde derivatives via reduction with LiAlH4 and then oxidation with PCC. Allylation reaction of corresponding aldehydes with allylmagnesium bromide gave homoallylic alcohols. Finally, homoallylic alcohols were reacted with acryloyl chloride in the presence of a base to produce acrylate esters, then ring closing metathesis by second generation Grubbs’ catalyst yielded the final klavuzon derivatives. Additionally, synthesis of new five -unsaturated lactone derivatives was also completed. Vinylation reaction of corresponding aldehydes with vinylmagnesium bromide gave the allylic alcohols. Coupling reactions of these alcohols with 3-butenoic acid in the presence of DCC/DMAP yielded the ester. Ring closing metathesis of the related ester was studied by using 2nd generation Grubbs’ catalyst.Master Thesis Syntheses of Novel 4'-alkyl Substituted Klavuzon Derivatives(Izmir Institute of Technology, 2015) Kanbur, Tuğçe; Çağır, AliStyryl lactones, which are compounds isolated from natural sources, are known for their cytotoxic property against variety cancer cell lines. Goniothalamin is a well known member of stryl lactones, include α,β-unsaturated δ-lactone in its structure. Being a α,β-unsaturated δ-lactone subunit is an important structural feature. Since, Goniothalamin has a selective cytotoxic property for cancer cell lines with no significant cytotoxic activity toward non-malignant cells. Recent studies show that naphthalen-1-yl substituted α,β-unsaturated δ-lactone derivative has slightly better cytotoxic activity than (R)-goniothalamin. As a result of that naphthalen-1-yl substituted α,β-unsaturated δ-lactones derivative was named as klavuzon by Çağır Research group. In this study it is aimed to synthesize 4’-alkyl substituted klavuzon derivatives. Syntheses were started with the Cu catalayzed addition of Grignard reagents to ethyl 4-(bromomethyl)-1-naphthoate to achieve alkyl substitution. For lactone synthesis a well-known three steps synthesis was used starting from aldehyde. Thus 1-naphthoate esters first reduced to alcohol then oxidized to aldehyde by using LiAlH4 and PCC. These aldehydes were reacted with allymagnesium bromide then formed alcohols were acrylated with acryloyl chloride to yield the corresponding esters. Finally, target molecules were synthesised by ring closing metathesis by using 2nd generation Grubbs’ catalyst.