Ph.D. Theses
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Browsing Ph.D. Theses by Author "Acar, Ali Ersin."
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Item Aromatic carboxamides as non-steroidal inhibitors of CYP17 for the treatment of prostate cancer(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2015., 2015.) Köseoğlu, Ahmet.; Acar, Ali Ersin.Cancer is the most common neoplasm of the prostate in developed countries. Since up to 80 % of Prostate Cancer (PCa) proliferation depends on androgens, most patients take hormone therapy as first choice of treatment. The PCa cell proliferation occurs due to binding of these androgens to androgen receptor (AR) that is overexpressed on PCa cells. Therefore, when the androgens are segregated from the tumor cells, the proliferation of PCa cell will stop. Although the androgens are secreted from three different sites, namely the testes, adrenal glands, and PCa cells, androgen production depends on catalysis by one enzyme, CYP17, which is also known as P450-C17. Being a pivotal enzyme in the biosynthetic route to steroidal hormones, CYP17 has a key role in the conversion of progesterone and pregnenolone to androstenedione and dehydroepiandrostenedione (DHEA) respectively, which constitute as the direct precursors of 5α-dihydrotestosterone (DHT) and testosterone (T). Although Abiraterone was launched as a potent steroidal CYP17 inhibitor, it interferes with other steroidogenic enzymes leading to side effects such as hypokalemia, hepatic dysfunction, oedema, and hypertension. Due to the potential side effects of steroidal CYP17 inhibitors resulting from inhibition of other steroid receptors, there is a certain need to develop nonsteroidal inhibitors. In this study, several derivatives of a nonsteroidal lead compound were designed and synthesized in order to optimize its interaction with CYP17 enzyme. Throughout optimization process, bioisosterism was utilized as a rational drug design approach. Quinoline moiety was chosen as center of interest as it was hypothesized that similar to other CYP17 inhibitors, it could bind well to iron of the heme group of CYP17 enzyme. In order to perform a structure-activity relationship (SAR) study, a systematic synthesis of n-butyl substituted 8-amnionquinolines was done. A library of final products was built by synthesizing several aromatic carboxamides via coupling aromatic amines with aromatic carboxylic acids.Item Polymeric tubes prepared from poly (vinyl alcohol) fiber templates(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2016., 2016.) Çavuşoğlu, Jesmi.; Acar, Ali Ersin.; Küsefoğlu, Selim.In this study, the fabrication of covalently crosslinked polymeric tubes by using poly(vinyl alcohol) (PVA) fiber templates has been demonstrated. The crosslinking on the surface of PVA fiber templates was achieved by two different methods. In the first method PVA surface hydroxyl groups were reacted with difunctional crosslinkers. Crosslinking took place with several dialdehydes and diisocyanates, respectively. The conditions were adjusted to allow the reaction to occur only on the surface and unreacted PVA inner core was removed from crosslinked fibers. Tubular structures which have adjustable shell thicknesses were succesfully fabricated by glutaraldehyde (GA) and 1,6-hexamethylene diisocyanate (HMDI) crosslinked PVA microfibers. Ultraviolet-visible spectroscopy was used to investigate load/release properties of these tubular hydrogels with changing shell thicknesses. Fluorescein dye molecules were used for imaging and the succesful absorption of dye molecules inside the shells was observed by optical microscopy. Furthermore, hydrophilicity differences were predicted between the outer and the inner shells. The feasibility of this method in fabrication of nanotubes was also investigated. In the second method PVA fibers were first reacted with acryloyl chloride and 3-trimethoxysilyl propylmethacrylate, respectively, to get double bond functionalized PVA fibers. These pendant double bonds were used to photopolymerize the surface of PVA with other mono and/or difunctional acrylate monomers. It was observed that during dissolution of the inner core, the shells were ruptured which may be due to a rigid network formation by photopolymerization. Therefore, it was found that the first crosslinking method is more suitable to prepare such hollow structures whose shells can be adjusted in terms of crosslinking and thickness. It was concluded that such materials may have potential applications in entrapment and release of several molecules.Item Synthesis of novel potent drug molecules active against prostate cancer and investigation of bioactive properties of cyclopolymers obtained by raft polymerization(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2011., 2011.) Erkoç, Selda.; Acar, Ali Ersin.The first part of the thesis includes synthesis of novel potent drug molecules active against prostate cancer. Structure-based drug design (SBDD) approach was used to discover novel lead compounds active against CYP17 by the researchers Prof. Metin Türkay and Assoc. Prof. İ. Halil Kavaklı from the Koç University. They found a non-steroidal lead compound with the IC50 value of 35.65M. In this study, in order to increase the activity of the lead compound against the CYP17, lead optimization studies were done. Lead compound derivatives were evaluated on the computer generated model of CYP17. The compounds that have favorable energy values in docking studies were synthesized to be effective in nanomolar concentrations. Some of the synthesized compounds were subjected to biological tests in order to measure inhibitory effects of them on CYP17. IC50 value of the compounds that displayed favorable inhibitory activity on human CYP17 were calculated. As a result, a new compound with the IC50 value of 2.3 M was discovered. The activity of this compound is about fifteen times higher than the activity of the lead compound. The second part of the thesis includes the investigation of bioactive properties of cyclopolymers obtained by Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization. In this study, RAFT polymerization was applied to symmetrical difunctional monomers, alkyl -(hydroxymethyl)acrylate (RHMA) ether dimers (R=alkyl (ethyl, n-butyl, tert-butyl, cyclohexyl, isobornyl)). The livingness of the obtained cyclopolymers with tert-butyl and isobornyl ester groups was shown through successful block copolymerization studies with n-butyl acrylate where the former was used as the macro-chain transfer agent (macroCTA). Finally, the antibacterial activities of the obtained cyclopolymers were investigated using Staphylococcus aureus and Escherichia coli as test organisms.