Ph.D. Theses

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Multifunctional monomeric and polymeric photoinitiators for free radical photopolymerization
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022., 2022) Gençoğlu, Türkan.; Semiz, Duygu Avcı.
In this study, novel polymerizable, polymeric and branched photoinitiators (PIs) were synthesized to attain high polymerization efficiency, migration stability, visible light absorption and water solubility to address environmental concerns. The photochemical and photophysical properties and photoinitiation mechanisms were investigated by electron-spin resonance, laser flash photolysis and steady-state photolysis techniques, as well as theoretical calculations. The performance of the photoinitiators was demonstrated for (photo)polymerizations of commercial monomers such as poly(ethylene glycol) diacrylate and 2-hydroxyethyl methacrylate. The first part of this thesis describes synthesis of novel thioxanthone and (bis)phosphonate functionalized poly(ethylene imine)s (PEI, Mw = 1800 g/mol) which can take part in dual curing process; in the first stage as the nucleophile and base for an aza-Michael reaction with acrylates, in the second stage as a photoinitiator in conjunction with iodonium salt (Iod). Also, charge transfer complexes (CTCs) formed between amines (PEI) and Iod can lead to free radical polymerization with or without irradiation in both stages. The second part describes two oligomeric photoinitiators prepared by integrating benzophenone (BP) alone or BP and phosphonate functionalities onto the oligo(amido amine) backbone. These PIs can generate radicals by CTC formation and by Type II photoinitiation at the same time under visible irradiation. The third part reports synthesis of a both polymeric and polymerizable PI, the first poly(-amino ester)- based PI, by the aza-Michael reaction of poly(ethylene glycol) diacrylate and 2-(2-aminoethoxy)-9H-thioxanthen-9-one. In the last part of this thesis, a cyclopolymerizable photoinitiator containing two Irgacure 2959 groups was synthesized by esterification reaction between 2,2’- (oxybis(methylene))diacrylic acid and Irgacure 2959. Its cyclic copolymer with di(tert-butyl) 2,2′-[oxybis(methylene)]bis(2- propenoate) was prepared by thermal polymerization.
Role of ionic liquids on the reactivity and selectivity of diels- alder reactions and single site catalysts
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022., 2022) Akgül, Deniz.; Doğan, İlknur.; Aviyente, Viktorya.
Ionic liquids (ILs) have gained interest because of their features such as high thermal stability, high chemical inertness, conductivity, their ability to dissolve organic and inorganic substances. It is possible to tune these properties offering advantages for a wide range of applications namely solutions, synthesis and catalysis. In this thesis, the solvent and ligand effects of ILs are investigated in the case of organic reactions and single-site catalysts (SACs) by using Density Functional Theory (DFT). Then, the influence of electron-donor/acceptor properties of the SACs on the catalytic activities and stabilities of Ir/Rh including complexes are examined by means of computational tools. Firstly, the role of ILs as solvents in the Diels-Alder reactions is modeled. The fact that ILs can have hydrogen bonding interac tions with the dienophiles, and thus significantly affect the endo selectivity and the rate of the Diels-Alder reactions has been assessed. The atomically dispersed catalysts in the pres ence of SiO2-, γ-Al2O3- and MgO supported-Ir(CO)2 complexes are analyzed in order to understand the support effects on the electronic properties of the active sites and stabilities of the catalysts. Chapter 5 deals with the electron-donor/acceptor properties of ILs by us ing IL coated/uncoated MgO supported Ir(CO)2 complexes in the presence of [Bmim][OAc] and [Bmim][PF6]. In order to understand the ligand effects on the catalytic properties of the SACs, ligand modification reactions between carbonyl and acetylene groups in the case of zeolite- supported Rh(CO)2 complexes are modeled by considering the proton mobility. Finally, the hydrogenation reaction mechanisms for 1,3-butadiene over γ-Al4O6 supported Ir(CO)2 complex is studied and the reasons behind the 1-butene selectivity have been clari fied. Overall, this study contributes to a better understanding of the solvent and ligand effects of ILs on the chemical reactions and the catalytic systems.
Molecular modeling of Bcl-xL post-translational modifications and of keteniminium salts
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022., 2022) Tanrıver, Gamze.; Çatak, Şaron.; Monard, Gérald.
Computational chemistry plays an important role in deciphering the structural proper ties of systems by using different approaches, such as quantum mechanics (QM) and molecular mechanics (MM) and gives insight by mimicking their dynamic environments. This dissertation contains two main topics, namely investigation of Bcl-xL deamidation via molec ular dynamics (MD) simulations and investigation of keteniminium salts via QM methods. Investigation of post-translational modifications (PTMs) is important to understand their role on the structure and function of proteins. Deamidation, one of the PTMs is a crucial switch used for regulating the biological function of anti-apoptotic Bcl-xL. In the first part of the thesis, deamidation-induced conformational changes in Bcl-xL were explored to gain insight into its loss of function by performing MD simulations. MD outcomes suggest that deamidation allosterically causes remarkable changes in conformation, interaction, and dynamics of Bcl-xL and conceivably impair its function. This study will provide a unique perspective on the underlying mechanism of Bcl-xL deamidation-induced cell death. Keteniminium salts (KIs), nitrogen analogues of ketenes are widely used intermediates for the synthesis of various organic substances due to their higher electrophilicity, reactivity and regioselectivity. In the second part of the thesis, KIs were scrutinized, from their forma tion mechanisms to their involvement in organic reactions, by means of a DFT study. Exper imentally observed reactivity differences in the [2 + 2] cycloaddition and electrocyclization reactions were rationalized via a range of different analysis techniques. The outcomes of this study are expected to contribute to the understanding of the formation mechanism as well as the reactivity differences of keteniminium salts and aid synthetic applications.
(BIS) phosphonate functionalized polymeric materials for biomedical applications
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022., 2022) Altuncu, Merve Seçkin.; Avcı, Duygu.
This work describes synthesis, characterization, and evaluation of (bis)phosphonate functionalized monomers, macromers and crosslinkers as well as their polymers and crosslinked networks for biomedical applications such as tissue engineering scaffolds, dental materials and targeted drug delivery. Various synthetic approaches were explored for incorporation of (bis)phosphonate functionality and tailoring of these materials’ properties such as degradation rate, mechanical moduli, mineralization ability, water solubility and hydroxyapatite affinity. In the first part, three novel phosphonate/phosphonic acid functionalized poly (β-amino ester) (PBAE) macromers with varying levels of hydophilicity were synthesized and homo- and copolymerized with poly(ethylene glycol) diacrylate (PEGDA) to fabricate networks with tunable degradation and mechanical properties. The second part reports synthesis of three novel phosphonic acid containing poly (amido amine) macromers and their homo- and copolymerization with 2- hydroxyethyl methacrylate to obtain hydrogels showing composition-dependent swelling, degradation and mineralization. In the third part, two different types of bisphosphonate/ bisphosphonic acid functional thermoresponsive polymers were synthesized (i) by copolymerization of three novel bisphosphonate functionalized acrylamide monomers containing different alkyl chains with N-isopropyl acrylamide, (ii) alendronate functionalization of a copolymer of NIPAM and 6- acrylamidohexanoic acid. In the last part, alendronate was incorporated into two carboxylic acid containing polymers (ibuprofen functionalized alkyl α-hydroxymethacrylate and 6- acrylamidohexanoic acid based polymers) via covalent and non- covalent interactions to enhance their hydroxyapatite affinity. The materials synthesized here have potential for (mostly bone-related) biomedical applications such as tissue engineering and targeted controlled drug delivery; and the methods can be used to fabricate more such materials, tailoring their properties to fit the desired application.
Redox-responsive biodegradable polymeric materials for biomedical applications
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2022., 2022) Çalık, Filiz.; Sanyal, Rana.; Sanyal, Amitav.
In recent years, biodegradable and stimuli-responsive polymeric materials have gained importance in cancer research and biomedical applications. Such materials can be used as implants in the body and a nano-sized drug delivery system. Within the scope of this thesis, three different stimulus- sensitive biodegradable polymer dendron conjugate systems were prepared, and micellar nanostructures were obtained with these structures. The hydrophobic drug was physically loaded into the micelle structures in the first three projects. In the first and second projects, a targeting group was used to increase the efficiency of the drug delivery system. These micellar carriers make the hydrophobic drug water-soluble in body fluid and use both passive and active targeting pathways to ensure that the drug is collected in tumor tissues. The size of micellar structures was appropriate in all three projects when examined in terms of their suitability for delivery based on the enhanced permeability and retention (EPR) effect. The first two projects used cyclic RGDfK as the targeting group. It was observed that the drugs incorporated into the micellar nanostructures with the targeting group accumulated more effectively in the breast cancer cells. Doxorubicin was used as a chemotherapy agent. The last study synthesized cryogels containing varying amounts of a thiol- reactive monomer. Facile and reversible functionalization of cryogels were demonstrated through the attachment of a fluorescent dye (Bodipy-SH) and bioactive ligands such as biotin-thiol and mannose-thiol to recognize Streptavidin and Concanavalin-A, respectively. The proteins bound to the cryogels were amenable to release through treatment with a thiol-containing reducing agent such as dithiothreitol (DTT). Overall, the novel thiol reactive macroporous cryogel structures will be a fascinating platform for various biomedical applications where a catch and release approach of analytes is necessary.
Synthesis of new dental adhesive monomers and polymers
(Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2006., 2006.) Albayrak, Aylin Ziylan.; Avcı, Duygu.
New phosphonate, phosphonic acid, carboxylic acid, iminodiacetate containing adhesive monomers based on alkyl-hydroxymethyl acrylates and their derivatives were synthesized. A new phosphonate-containing cyclic monomer was obtained from the reaction of 2-(2-chlorocarbonyl-allyloxymethyl)-acryloyl chloride with diethyl hydroxymethyl phosphonate. This monomer showed high cyclization tendency during homopolymerization and copolymerization with 2-(2-tert-butoxycarbonylallyloxymethyl)- acrylic acid tert-butyl ester (TBEED) using initiators 2,2’- azobis(isobutyronitrile) (AIBN) at 75-77 ºC. The Tg of the copolymers decreased with increasing amounts of phosphonate-containing monomer whereas the char residues of the copolymers increased. The selective hydrolysis of the phosphonate monomer with trimethylsilyl bromide gave a water soluble phosphonic acid-containing monomer. This monomer could not be homopolymerized but copolymerized with TBEED and its dicarboxylic acid derivative, 2-(2-carboxy-allyloxymethyl)-acrylic acid. A series of 4,4-disubstituted 1,6-heptadiene monomers were synthesized from the reaction of ethyl- -bromomethyl acrylate and tert-butyl- -bromomethyl acrylate with triethylphosphonoacetate and tetraethylmethylenediphosphonate using sodium hydride followed by selective hydrolysis of the ester groups. Photopolymerizations of the monomers were investigated to understand the effect of the cyclic monomer structure on their polymerization reactivity. A strong effect of the substituents at 2, 4 and 6 positions of the monomers on polymerization rate was observed. The polymerizability of the monomers were successfully correlated with the 13C-NMR chemical shifts of the vinyl carbons. Conversion values were consistent with the Tg being a measure of the flexibility of a monomer. The monomers containing phosphonic acid groups were soluble in water and ethanol. The acidic nature of the aqueous solutions of these monomers is expected to give them etching properties, important for dental applications. The interaction of the acid monomers with hydroxyapatite was investigated using 13C NMR technique. It was found that phosphonic acid-containing monomers demineralized the calcium phosphate in the HAP in preference to the carboxylic acid. Four new methacrylate monomers containing phosphonic and/or carboxylic acids were synthesized from the reaction of tert-butyl a-bromomethyl acrylate with triethyl phosphite followed by selective hydrolysis of the phosphonate or tert-butyl ester groups using trimethylsilyl bromide and trifluoroacetic acid. The copolymerization of these monomers with 2-hydroxyethyl methacrylate (HEMA) was investigated by photodifferential scanning calorimetry. The reactivities of the monomers increased by decreasing steric hindrance and increasing hydrogen bonding capacity due to hydrolysis of phosphonate or tert-butyl ester groups. Furthermore, new adhesive monomers with diethyliminodiacetate as a potential chelating group were synthesized from the reaction of ethyl-bromomethyl acrylate, 2-chloromethyl-acryloyl chloride and 2-(2-carboxy-allyloxymethyl)-acrylic acid with diethyl iminodiacetate. The monomers were homopolymerized and copolymerized with TBEED and HEMA. Rate of copolymerizations and conversions decreased with an increase in the monomer concentrations. Low polymerizability of these monomers were explained with the steric effect of the N,N-disubstituted methacrylamides and the presence of allyl amine group leading to degradative chain transfer. The monomers were hydrolyzed by potassium hydroxide solution and the salt derivatives were copolymerized with acrylamide in water using 2,2’-azobis(N,N’-amidinopropane) dihydrochloride (V- 50). Polymer yields after dialysis were low and decreased with increasing monomer concentrations. The Ni+2 chelating ability of the monomers were shown using UV-visible spectroscopy. Thermal stability of the copolymer increased on complexation with Ni+2 ions.
Analysis of the radical polymerizability of diallyl monomers
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2002., 2002.) Tüzün, Nurcan Şenyurt.; Aviyente, Viktorya.
In this study, the radical cyclopolymerization mechanism of diallylamine and diallyl ether monomers and their derivatives has been investigated by computational modeling. The calculations were performed by the Density Functional Theory using the B3LYP/6-31G* basis set. In the first part of the study, a correlation has been built between the stucture of the monomer and the polymerizability. The experimentally measured 13C NMR chemical shifts of the diallylamine monomers, which were in line with their polymerizabilities, could be successfully correlated to the descriptors derived from calculations. The charges, bond orders, reaction barriers have successfully reproduced the polymerizability trend. In the second and third parts of this study, the regioselectivities and stereoselectivities of ring closure reactions of diallylamine and derivatives have been explained by considering steric and electronic factors. Diallylamine monomers formed 5-membered rings even though the thermodynamically more stable 6-membered rings would be expected to form. It has been shown that the 5-membered rings have lower barriers for cyclization. The fourth part of the study includes the modeling of diallylether monomers and their derivatives. The fast and efficient polymerizability of diallylether monomer has been investigated by considering the similarities and differences between this compound and its amine analogue. In the last part of the study, the competing reactions, homopolymerization and H-transfer reactions, as well as standard cyclopolymerization reactions have been considered. The efficiencies of the competing reactions have been investigated in their relation to the standard cyclopolymerization reactions. Comparison of free energies of activation for cyclopolymerization and competing reactions has shown that competing reactions are less efficient in the case of cationic monomers
Preparation characterization and drug release behavior of thermo-and pH-responsive hydrogels and microspheres
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2002., 2002.) Taşdelen, Dinçer Betül.; Haliloğlu, Türkan.; Baysal, Bahattin M.,
In the present work, N-isopropylacrylamide/itaconic acid and N-isopropylacrylamide /maleic acid copolymeric hydrogels were prepared by irradiating the ternary mixtures of Nisopl- opylacrylamide/diprotic acid moieties (itaconic or maleic acid)/water by y-rays at ambient temperature. The influence of external stimuli such as pH and temperature of the swelling media on the equilibrium swelling properties were investigated. The hydrogels showed both temperature and pH responses. The effect of comonomer concentration and irradiation dose on the swelling equilibria and phase transition were studied. For the characterization of network structures of these hydrogels, molecular weight between cross-links and crosslinking densities were also determined. PNIPAAm microspheres (71-500pm) were prepared by using inverse suspension polymerization technique. The selected fraction (1 80- 250pm) was used for preparing NIPAAmIitaconic acid graft copolymer by radiationinduced surface modification technique. Finally, methylene blue, sildenafil citrate and lidocaine were used as model drugs for the investigation of drug adsorption and controlled release behaviour for the hydrogels and micospheres. Specific adsorption capacity of: hydrogels are found to increase with increasing amount of itaconic acid in the gel system. The effect of the initial drug loading amount, temperature and pH of the solution on the controlled release behaviour of the hydrogels were investigated. The release studies show that some of the basic parameters affecting the drug release behaviour of the hydrogels are, pH and temperature of the solution.
Barriers to enantiomerization of 1-(o-ARYL) barbituric and -2-thiobarbituric acid derivaties
(Thesis (Ph.D.) - Bogazici University. Institue for Graduate Studies in Science and Engineering, 2002., 2002.) Oğuz, Semin Funda.; Doğan, İlknur.
In this study, 5,5-dimethyl-1-(0-aryl)barbituricI, 1-(0-ary1)barbituric and 1-(0-aryi)- 2-thiobarbituric acids have been synthesized by the reaction of the o-arylureas or the oaryl- 2-thioureas with the diethylmalonate or 1,l-diethyl-2,2-dimethyl malonate in the presence of sodiumethoxide, 5,5-dimethyl-1-(o-ary1)-2-thiobarbituric acids have been synthesized by the reaction of the o-aryl-2-thioureas with the dimethylmalonic acid in the presence of acetylchloride. The studied barbituric and 2-thiobarbituric acids are chiral due to nonplanar ground states. The aim of this study is to separate the enantiomers of the barbituric and 2-thiobarbituric acid derivatives by liquid chromatography on an optically active sorbent and subsequent racemization to obtain the activation energies for the racemization process. The chiralities of the compounds have been proved by 'H and 13c NMR spectroscopy. The enantiomers have been separated by liquid chromatography on chiral sorbents, triacetylcellulose or cellulose tris-(3,s-dimethylphenyl) carbamate. The optical activities of the separated enantiomers have been detected by CD spectrometer or polarimeter. Upon thermal racemization the activation barriers of the 5,5-dimethyl-1-(0- ary1)barbituric and -2-thiobarbituric acids have been determined by using liquid chromatography. The activation barrier of the 1-(0-toly1)barbituric acid has been determined by using dynamic NMR spectroscopy. The racemization mechanisms have been discussed with reference to the determined barriers. In addition, the keto-en01 tautomerization of the 1-(0-ary1)barbituric and 1-(0-ary1)-2-thiobarbituric acids have been investigated in different solvents by using 'H and I3c NhXR spectroscopy.
Water soluble, low migration and visible light photoinitiators for greener photopolymerization
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2021., 2021.) Eren, Tuğçe Nur.; Semiz, Duygu Avcı.
In this work, novel monomeric, polymeric and mesomeric (high enough molecular weight to provide lower migration but not high enough to be called a macromolecule) photoinitiators (PIs) were synthesized with the aim of achieving the “green” properties of migration stability, water solubility, biocompatibility and visible light absorption. Their properties and performances were examined in terms of photophysical and photochemical aspects. In the third chapter, the first cyclopolymerizable monomeric PI in the literature (TXdMA) was produced by introducing both TX chromophore and hydrogen donating tertiary amine functionality on its structure. The fourth chapter reports two water soluble mesomolecule photoinitiators (TXBP and BPBP), synthesized by the susbstitution of biocompatible bisphosphonic acid functional groups into TX and benzophenone (BP); the first such PIs in the literature. In the fifth chapter, a water soluble mesomolecule photoinitiator (TXBP2) was fabricated through bisphosphonate functionalization of TX. The sixth chapter reports synthesis of a TX-based water soluble polymeric photoinitiator (PAA TX) from the aza-Michael reaction of a poly(amido amine) to 9-oxo-9H-thioxanthen-2-yl acrylate. The last chapter describes the syntheses of two novel water soluble multifunctional polymeric photoinitiators (PEI-I2959-Ts and PEI-I2959) through incorporation of I2959 into branched poly(ethyleneimine) (Mw = 1800 g/mol).
TiO2 semiconductor photodegradation of substituted resorcinols: |kinetic and mechanistic studies
(Thesis (Ph.D.)- Bogazici University. Institute for Graduate Studies in Science and Engineering, 1999., 1999.) Ökte, Ayşe Neren.; İnel, Yüksel.
The photocatalytic degradation of 1,3-dihydroxybenzene (1,3-DHB) (resorcinol) and the substituted resorcinols, 3,5-dihydroxytoluene (3,5-DHT), 1,3-dihydroxy-5-methoxybenzene (1,3-DHMB) and 3,5-dihydroxybenzoic acid (3,5-DHBA) in the presence of aqueous suspensions of TiO2 are investigated kinetically and mechanistically. The effects of initial concentrations of the reactants, the pH of the medium, temperature, incident photon flux, and irradiation time are examined in detail. It is found that 1,3-DHB and 3,5-DHT obey pseudo-first order kinetics whereas 1,3-DHMB and 3,5-DHBA obey zero order kinetics. The Langmuir type of plot confirms that reactions take place on the surface of TiO2. 1,3-DHB, 3,5-DHT, and 1,3-DHMB are found to be most efficient at pH 9.0 while 3,5-DHBA had highest efficiency at its natural pH 4.4. The activation energy is found as 11.2 kJ/mol, 17.4 kJ/mol, 17.1 kJ/mol, and 10.3 kJ/mol for 1,3- DHB, 3,5-DHT, 1,3-DHMB, and 3,5-DHBA, respectively. Based on the relative photonic efficiency concept, the quantum yield is found as 0.34, 0.22, 0.35, and 0.38 for 1,3- DHB, 3,5-DHT, 1,3-DHMB, and 3,5-DHBA, respectively. Deposition of Fe3+, Ni2+, Zn2+, Nb5+, Ta5+, Co2+, Mn2+, Al3+, Cr3+ and V4+ on the surface of TiO2 affects the photocatalytic degradation of reactant molecules. Fe3+ showed the highest efficiency.
Smart polymeric carriers :|targeted delivery of therapeutic agents
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2019., 2019.) Karaçivi, Merve.; Sanyal, Rana.; Sanyal, Amitav.
In cancer research, studies about polymer drug conjugates and targeted delivery of chemotherapy agents are gaining great attention due to their ability to enhance biodistribution profiles and improve efficacy of chemotherapy agents. In the scope of this thesis four different polymer drug conjugates were synthesized using acrylate based carriers. In each case, drug molecules were covalently attached to the polymeric carrier through biodegradable linkers. These polymeric carriers aim to accumulate the active drug in the tumor via passive and active targeting. Each carrier, due its size, has the capacity to take advantage of enhanced permeation and retention (EPR) effect. Along with the size, active targeting via small molecule targeting units are also utilized. As such, in the first project, anti-angiogenic drug Combretastatin A4 (CA4) was conjugated to polymer backbone through a hydrolyzable ester linker. A second drug, alendronate (ALN) was also conjugated to the system as a bone targeting agent aiming to accumulate the conjugate in bone tissue. For the next three studies, anti-neoplastic agent Docetaxel (DTX) and 5-Fluorouracil (5-FU) derivatives were used as the active drug moiety. These constructs were ornamented further to accumulate in breast and ovarian tumors. In each case, different linkers were utilized in order to affect the release profile of the abovementioned drug molecules. In vitro studies were undertaken to demonstrate the effect of the active agents on a variety of the cell lines.
Computational approaches to assess the binding properties of ligands :|the case of the NMDA receptor
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2019., 2019.) Haşlak, Zeynep Pınar.; Doğan, İlknur.; Aviyente, Viktorya.
One of the important issues in drug design is the identification of the biological activity of receptor ligands. Development, synthesis and activity measurements of ligands have a major importance in drug design. However, there are certain limits in experimental studies; synthesis of a large number of compounds to cover all the potentially active molecules is unrealistic. Computational studies could therefore provide a valuable aid to experimental studies on ligand design for glutamate receptors. By combining the strengths of Molecular Dynamics and Quantum Chemical approaches, a more focused inspection, characterisation and rationalization of the drug design studies is allowed to be established. In this dissertation, computational methods have been used to investigate the intrinsic properties of the biologically active molecules that cause the selectivity. The results of this study will be introduced in 4 chapters. In Chapters 4 and 5, we aimed to differentiate between agonists, antagonists and partial agonists based on Quantum Chemical descriptors and binding Gibbs free energies. Several molecular properties that could play a role in ligand binding to the glycine GluN1 subunit of NMDA and calculated binding Gibbs free energies were further used to provide a link between the efficacies and binding affinities of the ligands. Prediction of the acid dissociation constants of amino acids in proteins and ligands allows us to have information about the binding affinity and efficacy of the ligand to its target protein. Considering the significance of pKa’s, how atomic charges of carboxylic acids can be related to the prediction of pKa of the ligands have been explored in Chapter 6. In order to shed light on the origins of the stereoselectivity of biologically active ligands, several mechanistic pathways have been evaluated for 2-thiohydantoins which are potent androgen receptor antagonists and the results are given in Chapter 7.
Design and fabrication of novel reactive hydrogels for delivery of therapeutic agents and biomolecular immobilization
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2018., 2018.) Chambre, Laura.; Sanyal, Amitav.
Polymers have been widely used for the past decades as drug delivery systems owing to their attractive physical, chemical and mechanical properties. In this thesis, nanosized drug delivery systems were developed for the treatment of cancer, owing to their size and ability to target cancer cells via the enhanced permeability and retention effect. Also, cryogels were fabricated as an antibacterial patch and bio-immobilization support by virtue of their macroporous structure. In the first part, nanogels containing hydroxyl and maleimide groups were fabricated using an in-situ polymerization. Nanogels were decorated with doxorubicin, and a thiol-based dye, to act as a marker for imaging. As an improved version, in the subsequent chapter, multifunctional nanogels were fabricated by crosslinking copolymers using their thermo-responsive self-assembly in aqueous media. Obtained theranostic constructs were modified with doxorubicin, a dye and a targeting ligand, and they demonstrated enhanced internalization in breast cancer cells. In the third part, a porphyrin photosensitizer used for photodynamic and photothermal therapy in cancer was used as a crosslinker for fabricating nanogels. Obtained constructs generated singlet oxygen and killed breast cancer cells when excited at certain wavelengths. In the fourth part, furancontaining cryogels were utilized as a wound healing patch for the eradication of bacteria via release of a small molecule antibiotic and anti-microbial peptide, where the former was encapsulated and the latter was attached using the Diels-Alder reaction. Reduced graphene oxide incorporated into cryogels enabled photothermal heating. Upon heating drugs released by desorption from graphene oxide or through retro Diels-Alder reaction eradicated E. Coli and S. Aureus bacterial strains. As a final part of this thesis, novel thiol-reactive cryogels were fabricated and utilized as a platform for bio-immobilization and detection of proteins. In conclusion, various polymeric systems were fabricated and their possible application in different therapeutic areas was demonstrated.
Synthesis of mono/DI-[1-(2-anthryl)-1-phenylethylene] telechelic poly (methyl methacrylate), polystyrene, and polyisobutylene and related copolymerizations via photohemical reversible cycloaddition reactions
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2018., 2018.) Özgüç, Çimen.; Nugay, Turgut.
The synthesis of novel 1-(2-anthryl)-1-phenylethylene (APE) di-telechelic polyisobutylenes were done by the utilization of a difunctional cationic initiator and the in situ addition of the non-homopolymerizable APE monomer to the chain ends. Mono and di-anthryl telechelic polystyrenes and anthryl telechelic poly(methyl methacrylate)s were also synthesized via living anionic polymerization by the incorporation of APE at initiation or at chain end. Products were characterized by 1H NMR spectroscopy and Size Exclusion Chromatography (SEC). The polymers were irradiated with 365 nm and 254 nm UV light and the reversible photocycloaddition of anthryl moieties was investigated. Irradiations at 365 nm were conducted to obtain chain extension of anthryl and di-anthryl telechelic polymers; initially for homopolymer solutions and then for polymer mixtures. The chain extension of di-anthryl telechelic PIBs through photocoupling at 365 nm produced higher molecular weight products from low molecular weight precursors. The effect of precursor polymer concentration on the degree of chain extension was investigated, and intermolecular interactions leading to the formation of tetramers was observed. Intramolecular interactions leading to formation of cyclic products was also observed in some extent during the chain extension process, especially in the low concentration conditions. The photocoupled products were UV irradiated at 254 nm, which yielded partial reversal of photocycloaddition of anthryl groups and consequent photoscission of polymers. Products obtained by UV irradiations of mixtures of di-anthryl telechelic polyisobutylenes and polystyrenes at 365 nm were cast into films and their thermal and mechanical properties were investigated.
Synthesis and reactions of thioureas, their cyclized derivatives and oxazolidindiones
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2019., 2019.) Tunçel, Şenel Teke.; Doğan, İlknur.
In this study, several single enantiomer thioureas were synthesized and converted to their cyclic derivatives: 2-imino-thiazolidin-4-ones and 5-benzylidene derivatives. The conformations of the thioureas were determined in solution and in the solid state. In solution; an interconversion between the E,Z and Z,E conformations was observed with ΔG≠ values of around 50 kJ/mole. However in the solid state X-Ray crystal structure analyses revealed that they possess a Z,Z conformation. The thiazolidin-4-ones were found to be present only in the anti-conformation. Chiral hemiaminals were synthesized from the corresponding 2-iminothiazolidine-4-ones by LiAlH4 reductions stereoselectively and were converted to single enantiomer thiazol-2-imines by a water elimination reaction. The optical purities of thiazol-2-imines were proven by polarimetric measurements. The kinetics of the dehydration reactions which occured spontenaously both in the solid state and in solution were followed by time dependent 1H NMR spectroscopy. The corresponding first order rate constants and free energies of activation for the conversions were reported. It was found that the N-naphthalen-1-yl)ethyl derivatized hemiaminals were the most stable of all, the half-lives amounting to 267 days in the solid state and 96 hours in soluton. A series of axially chiral pyridine compounds carrying 2-iminothiazolidin-4one core were also reduced to their hemiaminal derivatives using LiAlH4. Due to the restricted rotation around the N3-aryl single bond, the M/P isomerization was observed. Single enantiomers of the new 5-methyl-3-aryloxazolidine-2,4-diones were synthesized by an asymmetric synthesis using chiral pool strategy and their optical purities were proven. Enantiomerically pure 5-methyl-3-aryloxazolidine-2,4-diones were reduced to their hemiaminal derivatives and ring opening products in the presence of LiAlH4 and NaBH4, respetively. Partial racemization was observed due to enolization of the molecules because of the acidic -hydrogen at C-5 of the ring during these reactions.
Stimuli responsive functional polymeric materials for biomedical applications
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2019., 2019.) Demirer, Hatice Betül.; Avcı, Duygu.
This work consists of synthesis, structural characterization and evaluation of stimuliresponsive functional polymers and hydrogels designed for biomedical applications. In the first project pH and redox responsive degradable gels and cryogels were synthesized from phosphonate-functionalized poly(-aminoester) macromers as potential materials for tissue engineering applications. Then injectable poly(-aminoester) based hydrogels were fabricated by a facile one-step method and a photosensitizer released from these hydrogels showed promising activity in phtodynamic therapy. Phosphonic acid containing acrylamides were synthesized and evaluated as self-etching dental adhesives. Furthermore, these acrylamides were used to make hydrogels which were then successfully mineralized to make bone-like composite materials. Lastly carboxylic acid-functional crosslinkers were fabricated into hydrogels, and the pH/redox response of these hydrogels were demonstrated through controlled release studies of R6G dye and resorcinol.
Novel functional hydrogels and polymer coated magnetic nanoparticles with degradable linkers for biomedical applications
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2017., 2017.) Aydın, Duygu.; Sanyal, Amitav.; Sanyal, Rana.
In this thesis, the design and fabrication of novel reactive interfaces such as hydrogels and polymer coated nanoparticles were investigated for applications related to the delivery of therapeutic agents. Randomly crosslinked hydrogels incorporating amine and thiol reactive groups that allow conjugation of various bioactive molecules in a releasable fashion were synthesized. Apart from using novel modes of conjugation and release from non-degradable hydrogel scaffolds, synthesis of a new class of degradable hydrogels with well-defined network structure was also established. Effective thioldisulfide exchange reaction based strategies were used to synthesize hydrogels where the crosslinked density could be changed and protein release profiles could be modulated. Importantly, very fast and complete degradation of these hydrogels to release the encapsulated protein was achieved. The first project involves preparation and functionalization of the amin reactive poly(ethylene glycol) (PEG) based bulk hydrogels and cryogels. Obtained activated carbonate containing 3D networks were evaluated as slow releasing drug reservoirs. In the second project, preparation of stimuli responsive welldefined polymeric networks with disulfide linkers was proposed. Hydrogels fabricated by different moleculer weight polymer were investigated in terms of their encapsulation and degradation behavior. In the third study, synthesize of cyclodextrin containing well-defined hydrogels and release behavior through thiol-disulfide exchange reaction were reported for controlled drug release application. In the fourth study, fabrication of functional hydrogels with dual functional monomers was demonstrated and functionalization and release studies were performed. In the final study, novel functionalizable polymer coated hydrophilic magnetic nanoparticles that contain thiol-reactive polymeric coatings were prepared via a „graft-from‟ approach to design pyridyl disulfide containing polymer coated magnetic nanoparticles.
Fabrication and functionalization of reactive polymeric coatings for biomedical applications
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2017., 2017.) Gevrek, Tuğçe Nihal.; Sanyal, Amitav.; Sanyal, Rana.
The work in this thesis describes the design and synthesis of novel reactive polymeric coatings that can be utilized for fabrication of functional interfaces for applications like biosensing and protective antibacterial coatings for implants. Various approaches were utilized to prepare these surface bound coatings as polymeric thin films, polymer brushes or hydrogels. In the first study, thermo-responsive polymeric films were prepared using furan containing copolymers and their reversible functionalization was demonstrated via Diels-Alder (DA)/retro Diels-Alder (rDA) strategy. The second study discloses fabrication of maleimide-containing thiol-reactive coatings on glass like surfaces and their functionalization using the nucleophilic thiol-ene reaction. In the third project, the maleimide-containing polymers were adapted for adhesion to metal surfaces via mussel inspired catechol based interaction. These surfaces were conjugated with antibacterial peptides, followed by assessment of their antimicrobial activity against bacteria. In the fourth project, maleimide containing polymer brushes were fabricated and appropriately functionalized brushes were employed for ligand-directed protein mediated immobilization of nanoparticles. In fifth study, amine-reactive polymer brushes containing succinimidyl-carbonate moieties amenable towards facile functionalization with amine-containing molecules were synthesized. In the final chapter, fabrication of multifunctional furan-protected maleimide-containing hydrogel coating on titanium surfaces that could be modified using UV-mediated thiol-ene, ieDDA, and after unmasking of the maleimide, with nucleophilic thiol-ene and DA reactions was described. In summary, in this thesis a variety of reactive polymer coated surfaces were fabricated and their efficient functionalization was demonstrated to highlight them as attractive candidates for various biomedical applications.
A theoretical investigation of solvent effect on the conformational equilibria of 2-substituted cyclohexanone ketal derivatives
(Thesis (Ph.D.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 1995., 1995.) Sağ-Erdem, Safiye.; Varnalı, Tereza.; Aviyente, Viktorya.
The conformational equilibria of 6-substituted-1,4-dioxospiro-[4.5]decanes and 7substituted-1,5-dioxospiro [5.5]undecanes, relatively complex polar systems, with substituents X=-CH3, -F, -CI, -CN, -OH, -OCH3, -N02 have been studied. The complete geometry optimizations have been carried out sequentially in the gas phase and in solution to represent the effect of the solvent. The methodology consists of the semiempirical PM3 hamiltonian and the self consistent reaction field computations. The effect of the solvent is implemented by the "cavity model". Ab initio calculations have also been performed on 1 ,1 , 2-trihydroxy ethane as a model for the hydroxy derivatives of the ketals studied.The discussion of the results is focused on the solvent effects arising from structural aspects, steric and electrostatic interactions on the axial/equatorial relative stability. The role played by multipole moments is considered. Good agreement with available experimental data and with previous theoretical studies has been obtained in general. The semiempirical methods and the simple solvent models are useful to predict the main role of solute-solvent interactions in conformational equilibria of complex systems for which ab initio calculations cannot be performed.

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