Phd Degree / Doktora
Permanent URI for this collectionhttps://hdl.handle.net/11147/2869
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Doctoral Thesis Studies Toward the Synthesis of Novel 1,4-Oxazepan and Coumarin Derivatives(01. Izmir Institute of Technology, 2022) Akbaş, Tuğçe; Çağır, AliIn this study it is aimed to synthesize potential novel MDM2 inhibitor which has 1,4-oxazepan-5-one skeleton. For this purpose (R)-(4-chlorophenyl)glycine was used as a starting material. Reduction of that with LiAlH4 and the protection of amine by Trt group was performed. After oxidation to aldehyde, direct or stepwise installation of glutaconic to the structure by either Michael type addition or coupling with amine by using HATU was quite problematic and all attempts were failed toward the preparation of this skeleton. Besides, synthesis of 1,4-oxazepan-5-one was also tried starting from chiral aminoalcohol and protected 5-hydroxy-2-pentanoic acid in two steps, first coupling then oxa-Michael addition. However this did not work well too. It seems that presence of activated methylene group might be the main problem in the addition of glutaconic acid reactions. In the second part of this thesis it was aimed to synthesize the 1,2,3-triazole substituted coumarin in order to investigate the potential antiproliferative properties of these over cancer cells. Acetylsalicilic acid was used as starting material in these syntheses. That was transformed 4-acetylene substituted coumarin derivatives as key intermediates then their transformations to corresponding final products was performed by click chemistry.Doctoral Thesis Characterization and Catalytic Applications of Hydrothermally Synthesized Poyoxotungstate Clusters Containing Organic-Inorganic Hybrid Materials(Izmir Institute of Technology, 2019) Ece, Özlem; Eanes, Mehtap; Çağır, AliMany scientists have been interested in hydrothermal synthesis and characterization of polyoxometalate clusters containing organic-inorganic hybrid materials recently because of having different applications in lots of fields, especially, using as catalysis in chemical reactions. In this study, three novel polyoxotungstate clusters were synthesized using hydrothermal method and catalytic activities of these three novel polyoxometalates and in addition two crystals previously synthesized in our group were studied. The first compound, [(4,4’-bpyH2)3][PCuW11O39] yellow crystals, crystallize in the space group P2(1)/n of the monoclinic system with four formula units in a cell. The crystal is a Keggin polyoxometalate and includes free 4,4’-bipyridine groups between the clusters. The second compound, (4,4’-bpyH2)[H2PW12O40]2.H2O colorless crystals, crystallize in the space group Ia-3 of the cubic system with twelve formula units in a cell. The crystal is a Keggin polyoxometalate and consists of two polyoxotungstate clusters, a free 4,4’-bipyridine group and a water molecule. The third and the last novel compound, (4,4’-bpyH2)4[H2P2W18O62]2 dark yellow crystals, crystallize in the space group P-1 of the triclinic system with four formula units in a cell. The crystal is a Wells-Dawson polyoxometalate and contains two polyoxotungstate clusters and free 4,4’-bipyridine groups between clusters. The catalytic study has been carried out using starch hydrolysis reactions by using hydrothermal synthesis and five different crystals were tried and conversion results were obtained. Starch samples converted to D-glucose with glucose yields above 90 wt.%. Catalyst reusability was performed for each crystal. No appreciable loss was observed in activity after five reaction cycles for each crystal.Doctoral Thesis The Investigation of Anticancer Properties of (r)-4'-methylklavuzon in Liver Cancer Cells and Liver Cancer Stem Cells(Izmir Institute of Technology, 2017) Delman, Murat; Çağır, Ali; Erdal, EsraHepatocellular carcinoma (HCC) is the fifth most seen cancer type and the third leading cause of death from cancers. HCC is a fatal disease and HCC patients have a 5-year survival rate of 14%. Discovery and identification of mechanisms of action for new therapeutic agents are required for a better treatment of HCC. One of the most important target in cancer treatment is the epigenetic acetylation of histones. Histone deacetylases (HDAC) and sirtuins provide chromatin compaction and transcriptional repression by removing acetyl groups from histone proteins and nonhistone proteins. Re-acetylation of chromatin and re-expression of tumor suppressor genes with the discovery of novel HDAC and/or sirtuin inhibitors are therapeutic targets in cancer research. In this study, (R)-4’-methylklavuzon was found to be cytotoxic in HuH-7 cells with IC50 values of 1.25 μM for HuH-7 parental cells, 2.5 μM for EpCAM+/CD133+ HuH-7 cells and 1.25 μM for EpCAM-/CD133- HuH-7 cells. It was observed that (R)-4’-methylklavuzon causes cell cycle arrest at G1 phase at 1.00 μM concentration in three cell populations, it induces apoptosis at 10 μM concentration at the end of 24 hours incubation. (R)-4’-methylklavuzon does not inhibit Class I/II HDACs in vitro whereas it causes inhibition of endogenous HDACs and/or sirtuins inside the cells sorted by MACS and FACS at 0.10 μM concentration. (R)-4’-methylklavuzon upregulates p21 expression significantly in HuH-7 cell populations to cause G1 arrest. It causes 45% inhibition in p53/MDM2 complex formation when examined with pure p53 and MDM2 proteins. Drug candidate causes 46% SIRT1 inhibition at 100 μM concentration in vitro whereas there was no inhibition of HDAC1 enzyme at the same concentration. SIRT1 protein levels in HuH-7 parental cells were upregulated to 240% within 24 hours of incubation with 3.00 μM of drug candidate. It was found that (R)-4’-methylklavuzon can also inhibit CRM1 protein providing increased retention of tumor suppressor proteins in the nucleus. p53 was overexpressed at 0.10 and 1.00 μM concentrations within 6 and 24 hours in HepG2 cells but slightly overexpressed in HuH-7 parental cells.Doctoral Thesis Asymmetric Synthesis of 5,6-Dihydro Derivatives(Izmir Institute of Technology, 2014) Akçok, İsmail; Çağır, Aliα,β-unsaturated lactone derivatives are very important structural core which are isolated from nature and shown as source for several biological activities. Biologically active styryl δ-lactones are well known α,β-unsaturated-δ-lactones. Up to date, many α,β- unsaturated-δ-lactones and their analogues have been isolated and synthesized, exhibiting promising anti-proliferative properties against different cancer cell lines. In this thesis, large scale asymmetric syntheses of (R)-4’-methylklavuzon and (R)- 2’-methylklavuzon were completed successfully. Also, syntheses of heteroatom functionalized naphthyl substituted novel α,β-unsaturated-δ-lactone (5,6-dihydro-2Hpyran- 2-one) derivatives, α,β-unsaturated-γ-lactone (furan-2(5H)-one) derivatives and 7- membered α,β-unsaturated lactone (6,7-dihydro-5H-oxepin-2-one) derivatives were accomplished. Development of a method for one-pot synthesis of 6-membered α,β-unsaturated- δ-lactone was also studied, and a new vinylogous aldol addition method was developed. By this method, new α,β-unsaturated methyl esters were prepared via dienolate formation starting with methyl buten-3-oate.