Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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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 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.Master Thesis Asymmetric Synthesis and Anti-Tumor Properties of Conformationally Constrained Analogues of (s)-And (r)-Goniothalamin(Izmir Institute of Technology, 2008) Kasaplar, Pınar; Çağır, AliNaturally isolated 5-substituted-a,B-unsaturated-.-lactones gained great attention of researchers due to their cytotoxic and anti-tumor properties. Styryl lactones are the most interesting members of this group of naturally available compounds. One of the well-known and important example for styryl lactone is goniothalamin, which shows cytotoxicity against variety of cancer cell lines. This cytotoxic property was shown to be selective for cancer cell lines with no significant cytotoxicity toward non-malignant cells. Recent structure activity relationship (SAR) studies on goniothalamin shows that R configuration on its stereogenic center, trans double bonded linker and Michael acceptor parts of the molecules are essential for its cytotoxic activity. In this study conformationally constrained analogues of (S)- and (R)-goniothalamin were synthesized. Syntheses were started with the catalytic asymmetric allylation of benzaldehyde, naphthaldehyde and quinaldehyde derivatives in the first step, then formed alcohols were acrylated with acryloyl chloride to yield the corresponding esters, in the last step, ring closing metathesis with Grubbs. catalyst yielded the target molecules. Meanwhile, in this study the synthesized 5-aryl-substituted-a,B-unsaturated-S-lactones were tested to determine their cytotoxicity against MCF-7, PC-3, DU-145 and LNCAP cancer cell lines.