Dissertations / Theses on the topic 'DNA Synthesis'
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1
Lo, Pik Kwan Peggy. "Supramolecular DNA chemistry: assembly of DNA nanotubes and templated synthesis of DNA-mimetic polymers." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95152.
Abstract:
DNA has emerged as a promising template for the programmable assembly of structures on the nanometer scale. In particular, DNA nanotubes hold promise for a number of biological and materials applications, because of their high aspect ratio and encapsulation potential. Current construction methods result in symmetrical and cylindrical assemblies that are totally double-stranded, and are long and polydisperse. In order to investigate DNA nanotubes for applications as well-defined molecular hosts and one-dimensional templates, better control over their geometry, stiffness and porosity, ability to encapsulate and length needs to be achieved. Specifically, the first section of this thesis will describe (a) a modular approach to construct DNA nanotubes of geometrically well-defined triangular and square-shapes, which can exist in either double- and single-stranded forms with different stiffnesses, (b) the construction of DNA nanotubes with longitudinal variation by alternating larger and smaller capsules along the tube length, the encapsulation of guest molecules within these DNA nanotubes as well as their selective release with externally added DNA strands, (c) the use of a DNA-templated approach to produce nanotubes with controlled pre-determined lengths of 1 μm, and 500 nm and narrow length distributions, and the encapsulation of gold nanoparticles within these well-defined nanotubes to form finite lines of gold nanoparticles with longitudinal plasmon coupling. While DNA is a very promising construction material, it suffers from serious drawbacks for practical applications in materials science and biology. DNA is difficult and expensive to obtain in large quantities, and has limited long-term stability. On the other hand, synthetic polymers are routinely used as building blocks for nanostructured materials, with multiple applications in areas ranging from optics and data storage, to separation science and biology. Thus, an important challenge is the creation ofL'ADN s'est récemment manifesté comme un matériau prometteur pour l'assemblage programmable de structures à l'échelle nanométrique. En particulier, les nanotubes d'ADN sont intéressants pour leurs applications en science des matériaux et en biologie, en raison de leur aspect linéaire et leur potentiel d'encapsulation. Les méthodes courantes de leur synthèse produisent des assemblées symétriques et cylindriques totalement constituées de doubles brins d'ADN longs et polydisperses. Afin d'examiner les nanotubes d'ADN pour leurs applications comme des hôtes moléculaires à structure bien-définie et comme modèles unidimensionnels, des méthodes de synthèse qui mènent à un plus haut niveau de contrôle de leur géométrie, rigidité, porosité, capacité d'encapsulation et longueur doivent être développées. Plus précisément, la première section de cette thèse décrira (a) une approche modulaire pour construire des nanotubes d'ADN géométriquement bien définis, triangulaires ou carrés, et pouvant exister en formes d'ADN double-brin ou brin simple avec des différences de rigidité, (b) la construction des nanotubes d'ADN avec une variation longitudinale, en alternant les grandes et les petites capsules le long du tube, et l'encapsulation de matériaux invités au sein de ces nanotubes d'ADN, ainsi que leur libération sélective sous l'action de brins d'ADN externes ajoutés, (c) l'utilisation de l'approche d'un modèle d'ADN pour produire des nanotubes avec des longueurs contrôlées et prédéterminées de 1 µm ou de 500 nm et des distributions de longueurs étroites, et l'encapsulation de nanoparticules d'or au sein de ces nanotubes bien définis pour former des lignes de longueurs bien définies de nanoparticules d'or avec un couplage plasmonique longitudinal. Bien que l'ADN soit une molécule très intéressante pour l'auto-assemblage de structures, son utilisation comme un outil dans les applications pratiques en science des maté
2
Araki, Kasumi. "Dual roles for DNA polymerase η in homologous DNA recombination and translesion DNA synthesis." Kyoto University, 2006. http://hdl.handle.net/2433/143860.
3
Porssa, Manuchehr. "Synthesis of radiosensitisers targeted to DNA." Thesis, Brunel University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305165.
4
Ellsmore, Victoria. "Human cytomegalovirus origin-dependent DNA synthesis." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340332.
5
Devadoss, Babho. "Probing the Base Stacking Contributions During Translesion DNA Synthesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1222818842.
6
Roberts, Lezah Wilette. "The synthesis of a tetracene quinone phosphoramidite photosensitizer to study charge migration through DNA." Thesis, Georgia Institute of Technology, 2001. http://hdl.handle.net/1853/30903.
7
Erler, Christiane. "Synthesis of Metallic Nanowires Using Integrated DNA Molecules as Templates." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-27671.
Abstract:
The DNA double helix is inherently a nanoscale wire-like object, possessing a 2 nm diameter as well as a remarkable capability for molecular recognition and the interaction with other chemical compounds, thus making it an attractive material for biologically driven assembly of artificial nanostructures. In this work methods for the construction of functional electronic networks from single DNA molecules are presented. For this, (i) the generation of patterns of distinct interconnects between micro-fabricated contact pads are explored by stretching end-specifically thiol-functionalized, single-tethered DNA molecules using hydrodynamic flow as well as an electric field-induced thermal flow. (ii) These networks then serve as a template for a selective in-situ photoinduced nucleation and growth of platinum clusters of 4 nm diameter along the DNA molecules. In the synthesis exclusively platinum ions from an aqueous platinum nitrate solution bonded electrostatically to the backbone of the immobilized DNA can be reduced upon irradiation with UV light, while background metallization is inhibited. Furthermore, the metallization scheme is applied to DNA nanotubes and another photochemical deposition process is used to tune the interparticle gap space in a discontinuous platinum cluster chain to form conducting nanowires. The "process toolbox'' presented in this work offers a versatile alternative for the hierarchical patterning and incorporation of biotemplated nanomaterials into micro-/nanofabrication schemesEin doppelhelikaler DNA-Strang besitzt mit seinem hohen Aspektverhältnis von Natur aus Ähnlichkeit mit einem Kabel. Zusammen mit seinen einzigartigen Selbstassemblierungseigenschaften sowie der Fähigkeit, mit einer Vielzahl von chemischen Stoffen eine Verbindung einzugehen, macht dies ihn zu einem aussichtsreichen Baumaterial für den Aufbau von künstlichen Nanostrukturen. In dieser Arbeit werden deshalb verschiedene Methoden für den Bau von elektronischen Schaltkreisen aus einzelnen DNA-Strängen demonstriert. Dazu wird (i) die Herstellung von Verdrahtungsmustern zwischen lithographisch gefertigten Kontaktstrukturen untersucht. Endständig mit Thiolgruppen funktionalisierte DNA-Moleküle, die an nur einem Ende mit der Oberfläche verknüpft sind, werden mittels Strömung oder eines elektrothermisch induzierten Flusses zwischen Elektroden gespannt. (ii) Diese Netzwerke dienen im Weiteren als Vorlage für ein selektives, lichtinduziertes Wachstum von Platinpartikeln mit Durchmessern von 4 nm lokal entlang der DNA-Moleküle. Dabei werden unter UV-Bestrahlung nur solche Platinionen reduziert, die aus einer Platinnitrat-Lösung elektrostatisch an die immobilisierte DNA angebunden haben. Partikelwachstum in der umgebenden Lösung wird weitgehend verhindert. Darüber hinaus wird dieses Verfahren auch auf DNA-Nanoröhren angewendet und ein weiterer photochemischer Abscheideprozess eingesetzt, um unterbrochene Clusterkettern zusammenzuwachsen, mit dem Ziel, elektrisch leitfähige Nanodrähte zu erhalten. Die vorgestellten Verfahren stellen eine vielseitige Alternative zu herkömmlichen, hierarchischen Fabrikationsschemen der Mikro- und Nanotechnologie dar
8
Stockley, Martin Lee. "Design and synthesis of selective DNA-dependent protein kinase (DNA-PK) inhibitors." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369816.
9
Kapusuz, Derya. "Sol-gel Synthesis Of Dna Encapsulated Silica." Master's thesis, METU, 2009. http://etd.lib.metu.edu.tr/upload/2/12610627/index.pdf.
Abstract:
Sol-gel processing routes for encapsulation of double stranded DNA in solid porous silica hosts have been established. The encapsulation was carried out in two steps: hydrolysis of a silica-forming alkoxide-based sol was followed by condensation/gelation to a solid form upon addition of a buffer solution containing DNA molecules. The effects of gelation chemistry and DNA amount on chemical and microstructural properties of resultant silica matrices and on DNA encapsulation efficiency were investigated. The analytical characterization was performed by UV-vis spectroscopy, 29Si nuclear magnetic resonance spectroscopy and by nitrogen adsorption studies. It was demonstrated that DNA incorporation had a pH-dependent catalytic effect on gelation kinetics and promoted silica network completion. In addition, the scale of porosity and the average pore size of the resultant silica increased with gelation pH and also with DNA-buffer solution in the starting sol-gel formulation. The chemistry-derived pore size variation controls the DNA encapsulation efficiency in the silica matrices and the DNA holding capacity strongly depends on the scale of the porosity attained.
The selective adsorption of ethidium bromide- a DNA-intercalative reagent molecule- on DNA-silica gels confirmed that the DNA molecules remained entrapped within the silica host in their native state without any deterioration. Besides pure silica, amine-functionalized hybrid silica hosts were also formed by sol-gel. The hybrid gels were found not to be suitable for DNA encapsulation, as these matrices dissolve in aqueous environment due to incomplete silica network formation. The DNA-doped silica hosts may provide promising matrices for development of biosensors, bioreactors and bioassay platforms.
10
Gilea, Manuela Aurora. "DNA and RNA synthesis in ionic liquids." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485198.
Abstract:
The solid-phase synthesis of oligonucleotide derivatives such as phosphorothioates and phosphoroselenoates was investigated. Some ionic liquids containing the trlbexyl(tetradecyl)phosphonium cation and various anions proved to be very effective in dissolving the chalcogens (sulfur and , selenium) and to prepare oligonucleoside chalcogenophosphates. The suitability ofionic liquid-based chalcogen-transfer mixtures for the synthesis of oligonucleoside chalcogenophosphates on solid-phase was evaluated and subsequently the structure-activity relationship studied in detail. The compatibility of ionic liquid-based chalcogen-transfer mixtures with diverse types of solid supports e.g. controlled-pore glass, poly(vinylacetate) and. different synthetic methods. e.g. phosphoramidite and H-phosphonate method makes them useful as replacement of the more expensive and relatively unstable commerciaily avai1able chalcogen-transfer reagents. The distillation of ionic liquids was also studied.
11
Baccaro, Anna [Verfasser]. "Enzymatic Synthesis of Functionalized DNA / Anna Baccaro." Konstanz : Bibliothek der Universität Konstanz, 2010. http://d-nb.info/1029291632/34.
12
Chow, Brian 1978. "Photoelectromechanical synthesis of low-cost DNA microarrays." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42405.
Abstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2008.Includes bibliographical references.
Recent advances in de novo gene synthesis, library construction, and genomic selection for target sequencing using DNA from custom microarrays have demonstrated that microarrays can effectively be used as the world's cheapest sources of complex oligonucleotide pools. Unfortunately, commercial custom microarrays are expensive and not easily accessible to academic researchers, and technical challenges still exist for dealing with the small amount of DNA synthesized on a chip. Genomic research would certainly benefit from the creation of cheaper custom microarrays with larger oligonucleotide concentrations per spot. This thesis presents the development of a novel DNA microarray synthesis platform based on semiconductor photoelectrochemistry (PEC) designed with these needs in mind. An amorphous silicon photoconductor is activated by an optical projection system to create "virtual electrodes" that electrochemically generate protons in a site-selective manner, thereby cleaving acid-labile dimethoxytrityl protecting groups with the spatial selectivity that is required for in-situ DNA synthesis. This platform has the potential to be particularly low-cost since it employs standard phosphoramidite reagents, visible wavelength optics, and a cheaply microfabricated and reusable substrate. By incorporating a porous thin-film glass that dramatically increases the DNA quantity produced by over an order of magnitude per chip, this platform may also simplify the handling of DNA cleaved from chip and drive down the cost per base synthesized. The hybridization detection of single-base errors was successfully demonstrated on PEC synthesized microarrays. This thesis also reports a suite of new surface chemistries and high-resolution techniques for patterning biological molecules.
by Brian Yichiun Chow.
Ph.D.
13
Schilter, David. "Synthesis and DNA-binding of Metallocyclic Architectures." Thesis, The University of Sydney, 2009. http://hdl.handle.net/2123/5317.
Abstract:
A new family of cationic N-heterocyclic ligand derivatives was prepared and characterised. Among these compounds are halide salts of the dications [Y(spacer)Y]2+, each of which comprise two N heterocyclic donor groups (Y = 4,4′-bipy, pyz, apyz, apym) linked by a conformationally flexible spacer such as (CH2)n, α,α′-xylylene, 2,6-lutidylene or thiabicyclo[3.3.1]nonane-2,6 diyl. The diquaternary halide salts were converted to NO3- and PF6- salts, and interaction of these bridging ligands with labile palladium(II) and platinum(II) precursors afforded several multinuclear complexes. Bis(4,4′-bipyridinium) dications were incorporated into the dinuclear macrocycles [M2(2,2′ bipy)2{4,4′ bipy(CH2)n4,4′-bipy}2]8+ (M = Pd, Pt; n = 4, 6), cis [Pd2Cl4{4,4′ bipy(CH2)34,4′-bipy}2]4+, [Pt2(dppp)2{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]8+ and cis-[Pt2Cl4{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]4+. While bis(pyrazinium) analogues were unreactive towards the palladium(II) and platinum(II) precursors, the doubly deprotonated bis(3 aminopyrazinium) and bis(2 aminopyrimidinium) derivatives served as charge-neutral quadruply-bridging ligands in the complexes [Pt4(2,2′ bipy)4{apyz(CH2)6apyz–2H}2]8+ and [Pt4(2,2′ bipy)4{apym(CH2)5apym–2H}2]8+, both of which feature Pt(II). Pt(II) interactions. Larger species formed when the diamine O,O′-bis(2-aminoethyl)octadeca(ethylene glycol) (PEGda) was treated with cis dinitratopalladium(II) and platinum(II) precursors. The resulting complexes [M(N,N)(PEGda)]2+ (M = Pd, Pt; N,N = 2,2′-bipy, en, tmeda) possessed great size (62 membered chelate rings) and aqueous solubility. DNA-binding studies were conducted with selected complexes in order to investigate the types of interactions these species might participate in. Equimolar mixtures containing either the 16mer duplex DNA D2 or the single strand D2a and palladium(II)/platinum(II) complexes were prepared and analysed by negative-ion ESI MS. Studies of D2/Pd(II) mixtures suggested extensive fragmentation was occuring, and the use of [Pd(tmeda)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+ resulted in D2 adducts of [Pd(tmeda)]2+ and [4,4′-bipy(CH2)44,4′-bipy]2+, respectively. Decomposition also occurred when D2a was used, although 1 : 1 adducts were observed with [Pd(tmeda)(PEGda)]2+, [Pd(2,2′ bipy)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. The low intensities of these adducts indicated that they are unstable towards ESI MS. Analogous ESI-MS experiments using platinum(II) derivatives were performed and, in contrast to those with palladium(II), indicated that the complexes remained largely intact. ESI-MS analysis of D2/Pt(II) mixtures allowed for the detection of 1 : 1 D2 adducts of [Pt(en)(PEGda)]2+, [Pt(tmeda)(PEGda)]2+ and [Pt2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. Intensities of the adduct ions suggested the greater charge and aryl surface area allow the dinuclear species to bind D2 most strongly. Both [Pt(2,2′-bipy)(Mebipy)2]4+ and [Pt(2,2′ bipy)(NH3)2]2+ gave rise to 1 : 2 adducts of D2, although the latter was found to be a weaker binder, perhaps owing to its lower charge. Data obtained using 1 : 5 (D2 : complex) mixtures were consistent with the results above and suggested that D2 can bind more molecules of daunomycin than any of the platinum(II) species. Analyses of D2a/Pt(II) mixtures gave results similar to those obtained with D2, although fragmentation was more pronounced, indicating that the nucleobases in D2a play more significant roles in mediating decomposition than those in D2, in which they are paired in a complementary manner. Investigations into the effects of selected platinum(II) complexes on the thermal denaturation of calf-thymus DNA (CT-DNA) in solution were conducted. Both [Pt2(2,2′ bipy)2{4,4′-bipy(CH2)64,4′-bipy}2]8+ and [Pt(2,2′-bipy)(Mebipy)2]4+ greatly stabilised CT-DNA, most likely by intercalation. In contrast, [Pt(tmeda)(PEGda)]2+ and [Pt(en)(PEGda)]2+ (as well as PEGda) caused negligible changes in melting temperature (∆Tm), suggesting that these interact weakly with CT-DNA. Data for [Pt(2,2′ bipy)(PEGda)]2+ and [Pt(2,2′-bipy)(NH3)2]2+ indicated that these species perhaps intercalate CT-DNA, with similar ∆Tm values for both complexes implying that PEGda does not play a major role in binding. While findings from ESI-MS experiments were similar to those from the thermal denaturation experiments, discrepancies between results from the two methods could be found. In particular, fragmentation of cyclic species during ESI-MS caused the binding strength of the species to be underestimated when this method was employed.
14
Schilter, David. "Synthesis and DNA-binding of Metallocyclic Architectures." University of Sydney, 2009. http://hdl.handle.net/2123/5317.
Abstract:
PhDA new family of cationic N-heterocyclic ligand derivatives was prepared and characterised. Among these compounds are halide salts of the dications [Y(spacer)Y]2+, each of which comprise two N heterocyclic donor groups (Y = 4,4′-bipy, pyz, apyz, apym) linked by a conformationally flexible spacer such as (CH2)n, α,α′-xylylene, 2,6-lutidylene or thiabicyclo[3.3.1]nonane-2,6 diyl. The diquaternary halide salts were converted to NO3- and PF6- salts, and interaction of these bridging ligands with labile palladium(II) and platinum(II) precursors afforded several multinuclear complexes. Bis(4,4′-bipyridinium) dications were incorporated into the dinuclear macrocycles [M2(2,2′ bipy)2{4,4′ bipy(CH2)n4,4′-bipy}2]8+ (M = Pd, Pt; n = 4, 6), cis [Pd2Cl4{4,4′ bipy(CH2)34,4′-bipy}2]4+, [Pt2(dppp)2{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]8+ and cis-[Pt2Cl4{4,4′-bipy(1,2-xylylene)4,4′-bipy}2]4+. While bis(pyrazinium) analogues were unreactive towards the palladium(II) and platinum(II) precursors, the doubly deprotonated bis(3 aminopyrazinium) and bis(2 aminopyrimidinium) derivatives served as charge-neutral quadruply-bridging ligands in the complexes [Pt4(2,2′ bipy)4{apyz(CH2)6apyz–2H}2]8+ and [Pt4(2,2′ bipy)4{apym(CH2)5apym–2H}2]8+, both of which feature Pt(II). Pt(II) interactions. Larger species formed when the diamine O,O′-bis(2-aminoethyl)octadeca(ethylene glycol) (PEGda) was treated with cis dinitratopalladium(II) and platinum(II) precursors. The resulting complexes [M(N,N)(PEGda)]2+ (M = Pd, Pt; N,N = 2,2′-bipy, en, tmeda) possessed great size (62 membered chelate rings) and aqueous solubility. DNA-binding studies were conducted with selected complexes in order to investigate the types of interactions these species might participate in. Equimolar mixtures containing either the 16mer duplex DNA D2 or the single strand D2a and palladium(II)/platinum(II) complexes were prepared and analysed by negative-ion ESI MS. Studies of D2/Pd(II) mixtures suggested extensive fragmentation was occuring, and the use of [Pd(tmeda)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+ resulted in D2 adducts of [Pd(tmeda)]2+ and [4,4′-bipy(CH2)44,4′-bipy]2+, respectively. Decomposition also occurred when D2a was used, although 1 : 1 adducts were observed with [Pd(tmeda)(PEGda)]2+, [Pd(2,2′ bipy)(PEGda)]2+ and [Pd2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. The low intensities of these adducts indicated that they are unstable towards ESI MS. Analogous ESI-MS experiments using platinum(II) derivatives were performed and, in contrast to those with palladium(II), indicated that the complexes remained largely intact. ESI-MS analysis of D2/Pt(II) mixtures allowed for the detection of 1 : 1 D2 adducts of [Pt(en)(PEGda)]2+, [Pt(tmeda)(PEGda)]2+ and [Pt2(2,2′-bipy)2{4,4′-bipy(CH2)44,4′-bipy}2]8+. Intensities of the adduct ions suggested the greater charge and aryl surface area allow the dinuclear species to bind D2 most strongly. Both [Pt(2,2′-bipy)(Mebipy)2]4+ and [Pt(2,2′ bipy)(NH3)2]2+ gave rise to 1 : 2 adducts of D2, although the latter was found to be a weaker binder, perhaps owing to its lower charge. Data obtained using 1 : 5 (D2 : complex) mixtures were consistent with the results above and suggested that D2 can bind more molecules of daunomycin than any of the platinum(II) species. Analyses of D2a/Pt(II) mixtures gave results similar to those obtained with D2, although fragmentation was more pronounced, indicating that the nucleobases in D2a play more significant roles in mediating decomposition than those in D2, in which they are paired in a complementary manner. Investigations into the effects of selected platinum(II) complexes on the thermal denaturation of calf-thymus DNA (CT-DNA) in solution were conducted. Both [Pt2(2,2′ bipy)2{4,4′-bipy(CH2)64,4′-bipy}2]8+ and [Pt(2,2′-bipy)(Mebipy)2]4+ greatly stabilised CT-DNA, most likely by intercalation. In contrast, [Pt(tmeda)(PEGda)]2+ and [Pt(en)(PEGda)]2+ (as well as PEGda) caused negligible changes in melting temperature (∆Tm), suggesting that these interact weakly with CT-DNA. Data for [Pt(2,2′ bipy)(PEGda)]2+ and [Pt(2,2′-bipy)(NH3)2]2+ indicated that these species perhaps intercalate CT-DNA, with similar ∆Tm values for both complexes implying that PEGda does not play a major role in binding. While findings from ESI-MS experiments were similar to those from the thermal denaturation experiments, discrepancies between results from the two methods could be found. In particular, fragmentation of cyclic species during ESI-MS caused the binding strength of the species to be underestimated when this method was employed.
15
Zheng, Qinguo. "Chemical synthesis of DNA containing modified bases by post-synthetic substitution and application of modified DNA to the study of protein-dna interaction." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261892.
16
Ghosh, Sumana. "Design And Synthesis Of Novel Interacalator Based Chemical Nuclease." Thesis, Indian Institute of Science, 2001. http://hdl.handle.net/2005/260.
Abstract:
Deoxyribonucleic acid and ribonucleic acid under physiological condition are polyanions composed of heterocyclic bases linked through sugar phosphate backbone. Due to Watson-Crick base pairing, DNA exists in double-helical form between two antiparallel strands of nucleic acid. Different conformations of DNA is possible among which the B-DNA form is considered to be the most common, and it is a right-handed double-helix with base pairs stacked at the center. There are two well-defined grooves termed as major and minor grooves, each has characteristic width and depth. Most of the DNA binding proteins generally approach DNA through the major groove, while small molecules such as drugs, antitumor antibiotics,1 their synthetic analogue,2 carcinogens,3 and the transition metal complexes4 interact with DNA through minor groove.
The nucleic acids function in the storage and transfer of genetic information. The function of cell expressions of proteins, synthesis of all bio-materials are directly or indirectly governed by the nucleic acid present in the body. Not only that, the origin of many diseases lie behind the structural modification or alterations in nucleic acids occur beyond our control.5 There are different drugs both natural and synthetic which are important in antibiotic chemotherapy, act against these diseases by interacting with DNA. Now to understand the actual mechanism of many diseases, how drugs interact with DNA and its specificity, binding sites of DNA, we need to develop molecules that modify or interact with biological molecules and such molecules can probe various structural aspects and type of interaction of macromolecular association complexes. One of such probe is the DNA cleaving agent. The potential scope of the utility of these compound is enormous and ranges from the creation of synthetic restriction enzymes for use by molecular biologists to the development of chemotherapeutic agents (Fe(BLM), calicheamicin) that may be effective against a variety of neoplastic diseases. They can also act as a structural probe (e.g. Fe(EDTA)2), drug / protein-DNA footprinting agent and affinity cleaving agent.
17
Loh, Ern. "Dissecting genetic and structural determinants of accurate DNA synthesis by DNA polymerase I /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5007.
18
Yakisich, Juan Sebastián. "Regulation of ongoing DNA synthesis in normal and neoplastic brain tissue /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-433-3/.
19
Rowan, Andrea Leah Margaret. "hDREF, a MEF2 sensitive regulator of DNA synthesis." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/26393.
Abstract:
The Myocyte Enhancing Factor 2 (MEF2) family of proteins have been implicated in a wide variety of cellular mechanisms including: muscle and neuronal differentiation, inhibition of apoptosis, upregulation of c jun expression, and embryonic and post-natal cardiac development. In the course of my research I have identified a novel MEF2-responsive gene referred to as h&barbelow;uman D&barbelow;NA R&barbelow;eplication Related E&barbelow;lement F&barbelow;actor (hDREF). Three putative MEF2 consensus-binding sites have been found within the two untranslated regions (UTRs) of the hDREF sequence (which lie 5' and 3' to the open reading frame). Using CHromatin I&barbelow;mmunolP&barbelow;recipitation (CHIP) assays I have shown that MEF2 proteins associate with the MEF2 binding site found within the 5'UTR of hDREF under both growth and differentiation conditions. Furthermore, mutation of the MEF2 binding sites results in a failure to repress expression, which indicated that MEF2 acts to negatively regulate hDREF expression during differentiation. Endogenous expression studies indicate that hDREF is highly expressed during growth and downregulated during differentiation. Functional studies suggest that hDREF is directly involved in regulating DNA synthesis, and that overexpression of hDREF leads to aberrant DNA replication in post-mitotic cells leading to polyploidy. Based on my research I propose that hDREF represents a novel MEF2 regulated gene, and that the primary function of hDREF is to ensure DNA synthesis with the cell cycle.
20
Burlinson, B. "Unscheduled DNA synthesis as an indicator of genotoxicity." Thesis, Swansea University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.636182.
Abstract:
The escalating production of new chemical entities and the rising cost of long term toxicity studies has necessitated the development of a number of short-term terms. This thesis details the development and initial validation of assays in which the end point investigated was the measurement of DNA excision repair i.e. unscheduled DNA synthesis (UDS). Initially the assay was developed in primary rat hepatocytes and later progressed so that the exposure to the test material took place in vivo with subsequent radiolabelling of the repair sites taking place in vitro. In both cases the amount of repair taking place was measured by autoradiography. Due to the insensivity of the liver UDS assay to some classes of genotoxin and a requirement to measure effects in tissues other than the liver a second assay was designed which again used UDS as the end point but for which the test organ was the stomach, specifically the glandular mucosa. Using the special architecture of the mucosa a system was developed where UDS could be measured (after in vivo exposure to the test agent and radiolabel) by scintillation counting. A number of test agents were investigated including known carcinogens, gastric irritants and those activated in the stomach by nitrosation. Results of both assays are given and their relevance to genotoxicity testing discussed.
21
Sadowski, John Paul. "Design and synthesis of dynamically assembling DNA nanostructures." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11272.
Abstract:
Kinetically controlled isothermal growth is fundamental to biological development, but it remains challenging to rationally design molecular systems that self-assemble isothermally into complex geometries via prescribed assembly and disassembly pathways. By exploiting the programmable chemistry of base pairing, sophisticated spatial and temporal control have both been demonstrated in DNA self-assembly, but largely as separate pursuits. This dissertation extends a new approach, called developmental self-assembly, that integrates temporal with spatial control by using a prescriptive molecular program to specify the kinetic pathways by which DNA molecules isothermally self-assemble into well-defined three-dimensional geometries.Chemistry and Chemical Biology
22
Clark, D. R. "Some aspects of DNA synthesis in Anabaena 2C." Thesis, University of Liverpool, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383453.
23
Dexter, Hannah R. "Synthesis and properties of DNA containing O6-pterosinBguanine." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/14418/.
24
Emig, Christopher Joseph. "Photoelectrochemical array platform for genomic scale DNA synthesis." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37200.
Abstract:
Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (leaves 56-58).
Molecular and synthetic biologists have increasing demand for large, high-fidelity constructs of synthetic DNA. Recent developments in harvesting oligonucleotides from DNA microarrays has proven that these can be assembled into large constructs of DNA for costs significantly less than traditional methods. This thesis presents a complete platform for the photoelectrochemical cleavage of protecting groups during in situ DNA synthesis. Photoelectrochemically patterned microarrays of phosphoramidite dye were produced with spot sizes of 100 um. This technology holds the potential for lowest cost per base pair of DNA produced over alternative microarray technologies, and may prove to be useful in de novo synthesis of large DNA constructs.
by Christopher Joseph Emig.
M.Eng.
25
Rospigliosi, Alessandro. "Improving the conduction of DNA by molecular synthesis." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613839.
26
Wilks, Thomas R. "Synthesis of DNA-polymer conjugates using RAFT polymerisation." Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/58568/.
Abstract:
The use of reversible addition–fragmentation chain transfer (RAFT) polymerisation for the production of DNA–polymer conjugates is explored. Chapter 1 gives a general introduction to the field of DNA–polymer conjugates, their potential applications and methods for their synthesis. The need for a general, solutionphase technique for DNA–polymer conjugation is highlighted. In Chapters 2-5, the use of a number of different strategies for the production of DNA–polymer conjugates is described. Amide coupling (Chapter 2) is found to produce the desired products only under very specific reaction conditions. The thiol–alkene Michael addition reaction (Chapter 3) is found to afford DNA–polymer conjugates in aqueous solution with high yield; however, attempts to replicate this using organic solvents are not successful. The inverse electron-demand Diels–Alder reaction between tetrazine and norbornene (Chapter 4) is explored and found to produce DNA–polymer conjugates in high yield in organic solvents; however, the precursor compounds are time-consuming to prepare and so the generality of this approach is limited. Finally, the copper-catalysed azide–alkyne cycloaddition (Chapter 5) is found to be an excellent method for the production of a wide range of DNA–polymer conjugates. Chapter 6 describes the use of the DNA segment of a DNA–polymer conjugate to assemble a discrete three dimensional nanostructure – a DNA tetrahedron – incorporating the temperature-responsive polymer poly(N-isopropylacrylamide). These hybrid structures are found to be able to stabilise the formation of discrete, well-defined polymer nanoparticles at elevated temperatures. Chapter 7 describes the use of a non-covalent interaction (intercalation) to produce DNA– polymer conjugates. The effect of polymer molecular weight and structure on the strength of this interaction are explored. Finally, intercalation is exploited to template the formation of discrete polymer particles on a DNA strand.
27
Whitfield, Colette J. "Enzymatic protocols for the synthesis of designer DNA." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3528.
Abstract:
The enzymatic synthesis of long DNA with a controllable sequence, length and functional content has been reported. This method, involves the heating and cooling of the reaction components, resulting in the extension of repeating units. The key components comprise of the oligo seed of interest, the deoxynucleotide triphosphates (dNTPs), and a DNA polymerase. Using a thermostable Thermococcus gorgonarius Family B DNA polymerase exonuclease minus variant, Z3, and 20 heat-cool cycles, long DNA up to 20,000 base pairs bearing repeating units between 1 to 40 bases was produced. Incorporation of artificial nucleotides, with modifications ranging from single atom exchanges, 5-I-dCTP, 7-deaza-I-dATP, 5-Br-dUTP and 6-S-dGTP, to long chains, 5-C8-alkyne-dCTP, was demonstrated. Modifications situated in the major groove have little effect on the DNA polymerase efficiency but reduced enzymatic processivity is observed if the modification lies in the hydrogen-bonding region. By tailoring the oligo seed, it is possible to synthesise long designer DNA to include modifications at user defined positions. The modified DNA product lengths are similar to the unmodified DNA products, except for 6‑S-dGTP, which yielded DNA of 500 base pairs. 6-S-dGTP is renowned for strong metal interactions, and was exploited for the specific localisation of Au+, Ni2+, Cd2+ and Au3+ at repeating G positions. As the final 6-S-DNA product is limited in length, an alternative thiol modification was investigated. Using phosphorothioate dNTPs, sulfur bearing DNA products similar in length to the unmodified DNA were produced after 30 heat-cool cycles. This enabled the specific positioning of Au-nanoparticles through careful oligo seed design. DNA bearing the 5-C8-alkyne-dCTP provides alkyne anchors at sites sitting in the major groove. To demonstrate the ability to add a second layer of design, click chemistry with azide-fluor-545 was investigated. This opens up potential routes to more complex modifications via organic synthesis at precise sites within the designer DNA.
28
Paniwnyk, Zennia. "Synthesis, DNA interactions and cytotoxicity of novel chloroethylaminoanthraquinones." Thesis, De Montfort University, 2000. http://hdl.handle.net/2086/13278.
Abstract:
The design of DNA directed nitrogen mustards has led to the development of compounds with increased specificity for DNA and enhanced cytotoxicity compared to similar untargeted mustards. By linking an intercalating anthraquinone chromophore to a nitrogen mustard function it was anticipated that such compounds would also have the potential to irreversibly inhibit the topoisomerase II (topo II) enzyme.
29
Mayer, Alain. "Synthesis and triplex forming properties of pyrrolidino-DNA /." [S.l.] : [s.n.], 2005. http://www.zb.unibe.ch/download/eldiss/05mayer_a.pdf.
30
Carneiro, Karina. "DNA - macromolecule conjugates: synthesis and hierarchical self-assembly." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119476.
Abstract:
The remarkable molecular recognition specificity of DNA, combined with its structural and biological properties, makes it useful as a programmable and addressable building block for materials science. The materials constructed from nucleic acids have expanded the role of DNA and RNA beyond biology, into a useful component of advanced synthetic materials. The study of DNA self-assembly is rapidly evolving and will most likely find new and unforeseen applications ranging from medicine and biology to nanoelectronics and nano-optics. The error-free and predictable self-assembly of DNA over many length scales is necessary for their use as components of nanodevices and in nanomedicine. The work within this thesis describes an investigation of the self-assembly properties of DNA-macromolecule conjugates with a goal towards predictable long-range order. Conceptually, the work presented in this thesis can be divided into three parts. (1) The first part describes methods to introduce the long-range order achieved by block copolymer assemblies into DNA strands. We present the synthesis of DNA amphiphiles and their hierarchical assembly into nanofibers and ordered networks. (2) In the second part, we use a monodisperse 3D DNA nanoconstruct to direct alkyl chain aggregation below their critical micelle concentration (CMC) through DNA's base pairing ability. (3) The last part describes the hierarchical placement of DNA amphiphiles and of their assemblies along DNA nanotubes. The work described herein offers insight into the synthesis and self-assembly properties of DNA-macromolecule conjugates, and into their hierarchical self-assembly with DNA nanostructures.En vertu de la fidélité de ses interactions supramoléculaires, ainsi que ses caractéristiques structurales et biologiques, l'ADN est un ajout programmable, contrôlable et, donc, extrêmement utile dans la science des matériaux. Face aux progrès établis dans ce domaine, le rôle de l'ADN et de l'ARN n'est plus restreint qu'à la biologie; en effet, les atouts des acides nucléiques en tant que composants de matériaux synthétiques avancés en sont plusieurs. L'étude de l'auto-assemblage de l'ADN est en évolution vive, axée plutôt vers des réalisations futures au niveau médical, biologique, nano-électronique et nano-optique. Pour que l'ADN adopte un rôle central au sein de la nanotechnologie et la nanomédecine, le contrôle de l'auto-assemblage sur plusieurs échelles de longueur est un prérequis absolu. Le travail réalisé dans cette thèse concerne l'auto-assemblage d'hybrides macromoléculaires d'ADN dans le but de pouvoir organiser ces derniers sur des longueurs au delà du nanométrique. Les concepts seront divisés parmi trois sous-thèmes: (1) La première partie propose des méthodes afin de pourvoir les assemblages de brins d'ADN d'un niveau d'ordre à longue échelle tel que connu chez les copolymères en bloc. Nous présentons la synthèse d'hybrides d'ADN à caractéristiques amphiphiles ainsi que leur assemblage hiérarchique en nano-fibres et en réseaux organisés. (2) Dans la deuxième partie, nous utilisons des assemblages uniformes d'ADN en 3D afin de diriger l'agrégation de chaines alkyles hydrophobiques en dessous de leur concentration micellaire critique (CMC) grâce à la complémentarité de l'ADN. (3) La dernière partie présente le placement hiérarchique de brins d'ADN amphiphiles, ainsi que de leurs assemblages, sur des nanotubes d'ADN. Les principes qui sont sortis de ces travaux démontrent la possibilité de maitriser la synthèse et l'auto-assemblage d'hybrides macromoléculaires d'ADN, ainsi que l'organisation hiérarchique de ceux-ci avec d'autres structures nanométriques à base d'ADN.
31
Chan, Kara Y. "MECHANISMS OF TRINUCLEOTIDE REPEAT INSTABILITY DURING DNA SYNTHESIS." UKnowledge, 2019. https://uknowledge.uky.edu/toxicology_etds/29.
Abstract:
Genomic instability, in the form of gene mutations, insertions/deletions, and gene amplifications, is one of the hallmarks in many types of cancers and other inheritable genetic disorders. Trinucleotide repeat (TNR) disorders, such as Huntington’s disease (HD) and Myotonic dystrophy (DM) can be inherited and repeats may be extended through subsequent generations. However, it is not clear how the CAG repeats expand through generations in HD. Two possible repeat expansion mechanisms include: 1) polymerase mediated repeat extension; 2) persistent TNR hairpin structure formation persisting in the genome resulting in expansion after subsequent cell division. Recent in vitro studies suggested that a family A translesion polymerase, polymerase θ (Polθ), was able to synthesize DNA larger than the template DNA. Clinical and in vivo studies showed either overexpression or knock down of Polθ caused poor survival in breast cancer patients and genomic instability. However, the role of Polθ in TNR expansion remains unelucidated. Therefore, we hypothesize that Polθ can directly cause TNR expansion during DNA synthesis. The investigation of the functional properties of Polθ during DNA replication and TNR synthesis will provide insight for the mechanism of TNR expansion through generations.
32
Brucale, Marco <1976>. "Design, synthesis and characterization of DNA supramolecular nanostructures." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2007. http://amsdottorato.unibo.it/474/1/Brucale_PhDthesis_2007.pdf.
33
Brucale, Marco <1976>. "Design, synthesis and characterization of DNA supramolecular nanostructures." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2007. http://amsdottorato.unibo.it/474/.
34
Ivanova, Tsvetomira Georgieva 1978. "The DNA damage and the DNA synthesis checkpoints converge at the MBF transcription factor." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/116932.
Abstract:
DNA damage is an ongoing threat to both the ability of the cell to faithfully transmit genetic information to its offspring as well as to its own survival. In order to maintain genomic integrity, eukaryotes have developed a highly conserved mechanism to detect, signal and repair damage in DNA, known as the DNA damage response (DDR). In fission yeast the two DDR pathways converge at the regulation of single transcriptional factor complex (MBF) resulting in opposite directions. We have shown that when the DNA-synthesis checkpoint is activated, Max1 is phosphorylated by Cds1 resulting in the abrogation of its binding to MBF. As a consequence, MBF-dependent transcription is maintained active until cells are able to overcome the replication challenge. In contrast, upon DNA damage, Chk1 the effector kinase of DNA damage checkpoint is activated and blocks the cell cycle progression, inducing DNA repair and repressing the MBF dependent transcription. We have revealed that Cdc10 is the target of the DNA-damage checkpoint and when cells are treated with MMS or are exposed to IR, Chk1 phosphorylates Cdc10 inducing the exit of MBF from chromatin. The consequence is that under these conditions, MBF-dependent transcription is repressed. Thus, Max1 and Cdc10 couple normal cell cycle regulation and the DNA-synthesis and DNA-damage checkpoints into MBF.
35
Li, Kaiyu. "Supramolecular Ruthenium(II) and Osmium(II) Complexes: Synthesis, Characterization, DNA Binding and DNA Photocleavage." University of Dayton / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1513235232385279.
36
Yu, Hongchuan. "Novel Cyclo Deoxynucleoside: Synthesis and Evaluation." Thesis, Boston College, 2012. http://hdl.handle.net/2345/2751.
Abstract:
Thesis advisor: Larry W. McLaughlinThesis advisor: Mary F. Roberts
Nucleic acids are essential biological molecules for life. For example, deoxyribonucleic acid (DNA) is the main genetic information carrier; ribonucleic acid (RNA) plays a critical role in translation and transcription. These characteristics place nucleic acids as the fundamental genetic materials of a living system. Since over a century ago, intensive attempts have been made by researchers to study the nucleic acid properties. For chemists, it is particularly interesting and important to understand the relationship between structures and properties of nucleic acids. For instance chemical modifications can alter stability of nucleic acids, and consequently influence their biochemical behaviors. In this work, we began by investigation of a 5',6-cyclo-modified nucleic acid resembling the product of DNA oxidation, and then developed a library of cyclomodifications. Our research on their structures and properties indicated that by installing cyclo-modifications we might be able to add some properties, that were not observed in nature to nucleic acids
Thesis (PhD) — Boston College, 2012
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
37
Muscat, Richard A. "Molecular motion and templated chemistry coordinated by DNA nanomachines." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572658.
Abstract:
This thesis investigates ways in which a nanoscale production line may be built from synthetic DNA components. One property of a production line is motion, the coordinated movement of components, in this case strands of DNA, between specific locations. Another property is the ability to assemble a product, where smaller molecular building blocks are attached to D A and react when brought together by the DNA assembly line. An important fea- ture of either task is the ability of the mechanism to proceed with minimum user interaction: it is preferable that the assembly line be autonomous. The challenges and design principles of molecular machines working in nano- scale environments are first considered. Previous studies demonstrating the use of synthetic DNA not only as a self-assembling material to build nano- structures, but also to coordinate motion, are summarized. All DNA nano- machines that operate through the exchange of DNA strands are coordinated by toeholds. A 'split toehold', one that combines two smaller toeholds on distal sections of DNA held in proximity, is proposed as a way to allow a single cargo strand to interact with many different components. A molecular motor is then developed that transports a cargo between track locations. The fuel strands are hairpins, that carry instructions directing the cargo to the next anchorage. The switching of cargo direction in response to the chemical environment is also investigated. Two mechanisms that may allow the autonomous assembly of components are investigated, one of which is demonstrated using DNA-linked cleavable molecular building blocks. Further extensions to the mechanism are investi- gated, for example, the ability to use the DNA mechanism itself as a barcode containing information on the order of assembled ingredients.
38
Onyemauwa, Frank Okezie. "Investigation of the Role of Groove Hydration and Charged Nucleosides in DNA Charge Transfer." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/11634.
Abstract:
Structural analyses of DNA oligonucleotides indicate the presence of bound water molecules in the major and minor grooves of DNA. These water molecules participate in DNA charge transfer by their reaction with guanosine radical cation to form 7,8-dihydro-8-oxo-guanine (8-oxoG), which when treated with a base leads to DNA strand cleavage. We probed the reaction of guanosine radical cation with water with series of alkyl substituted cytidines and thymidines by incorporating the modified nucleosides into anthraquinone linked DNA duplexes and irradiating them with UV light at 350 nm. The incorporation of these hydrophobic substituents disrupt the DNA spine of hydration, and we have observed that these modifications in the major and minor groove do not effect the trapping or long distance hopping of radical cations in DNA.
The second part of the work reported herein examines the role of charged nucleosides in long range charge transfer in duplex DNA. DNA methylation is a naturally occurring process mediated by enzymes responsible for such functions in biological systems. Hypermethylation of DNA can also occur as a result of environmental alkylating agents leading to mutation of the affected cells. Methylation of the ring nitrogen of a purine base can introduce a positive charge in the ring resulting in the cleavage of the glycosidic bond of the nucleoside.
To understand the role of a charged nucleoside on charge transfer in DNA, we designed and synthesized cationic nucleoside mimics, which were incorporated into anthraquinone-linked DNA strands and irradiated at 350 nm. The presence of the cationic bases on the duplexes inhibits the migrating hole from hopping along the DNA strand, and induces a prominent local structural distortion of the DNA as a result of the charged nucleobase.
39
Holzberger, Bastian [Verfasser]. "From Multi-fluorinated DNA Polymerases to Insights into DNA Synthesis by NMR spectroscopy / Bastian Holzberger." Konstanz : Bibliothek der Universität Konstanz, 2012. http://d-nb.info/1026847125/34.
40
Tetzlaff, Charles N. "Synthesis and evaluation of acylated DNA and RNA oligomers /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2001.
Abstract:
Thesis (Ph.D.)--Tufts University, 2001.Adviser: Clemens Richert. Submitted to the Dept. of Chemistry. Includes bibliographical references (leaves 228-235). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
41
Rahman, Khondaker Mirazur. "Design, synthesis and Evaluation of DNA interactive small molecules." Thesis, University College London (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509314.
42
Giles, Yvonne. "Synthesis, DNA interactions and activation of novel cytotoxic anthraquinones." Thesis, De Montfort University, 1999. http://hdl.handle.net/2086/10751.
Abstract:
Mitoxantrone is a dihydroxyanthracenedione derivative with significant clinical activity against advanced breast cancer, lymphoma and several types of leukaemia. However, as with all conventional anticancer agents, its non-specific nature results in dose-limiting systemic toxicity. The pharmacological (and toxicological) effects of mitoxantrone are thought to be mediated through its interaction with DNA and the DNA processing enzyme, topoisomerase II. Hence, an investigation of the DNA binding properties of mitoxantrone and related bis-substituted alkylaminoanthraquinones was undertaken with a view to developing agents with reduced toxicity to normal cells. DNA intercalation was evaluated using spectrophotometric and DNA thermal denaturation (Tm) techniques with calf thymus DNA. Overall, compounds that were hydroxylated at the 5 and 8 positions of the anthraquinone chromophore had increased DNA binding affinity compared to their non-hydroxylated analogues. The ~ Tms of mitoxantrone and its non-hydroxylated analogue ametantrone, were 26.4 °C and 21.5°C respectively. The affinity constants (K) for the chromophore-hydroxylated compounds were between 3.94 and 4.95 xl06M-1 while K values for their non-hydroxylated analogues were between 1.63 and 3.25 xl06M-l. For the di-N-oxide, AQ4N, intercalation was not detectable. The mono-N-oxide, AQ6N, showed modest DNA binding activity, with a ~Tm of7.0°C and an affinity constant of 3.64 Xl06M-l. Several of the alkylaminoanthraquinones were further investigated for their ability to inhibit decatenation of kDNA by topoisomerase II. Mitoxantrone and its analogues, AQ4 and AQ6, inhibited decatenation at concentrations ofO.75IlM, 1.51lM and 1.0llM respectively. In contrast, total inhibition of decatenation by the N-oxides, AQ4N and AQ6N, required concentrations of 50llM and 1 OIlM respectively. Hence modification of the terminal nitrogen on both alkylamino side chains to form a di-N-oxide resulted in a large decrease in DNA binding affinity and topoisomerase II inhibition. In view of the importance of the cationic alkyl amino side chains in intercalative binding and the enhanced ability of mitoxantrone to inhibit topoisomerase II, a series of acetalanthraquinones were synthesized. These compounds, referred to as YCG7 (1- substituted), YCG8 (l,4-bis-substituted), and YCG9 (l,5-bis-substituted), possessed dimethoxy groups in place of the alcohol groups of mitoxantrone, and were designed to be converted to their respective aldehydes, which should increase their cytotoxic activity due to their potential to form Schiffs bases with intracellular targets. The acetalanthraquinones were relatively poor DNA intercalators compared to the parent compound, ametantrone. The ~Tm values for YCG7, YCG8 and YCG9 were 3.6 °C, 14.2 °C and 15.7 °C respectively. The bathochromic shifts for the acetalanthraquinones in the presence of calf thymus DNA and 0.5M NaCl/0.008M Tris at a DNA:drug ratio of 10:1 were 1.4nm, 3.5nm and 3.6nm respectively for YCG7, YCG8 and YCG9 (ametantrone=12.2nm). Oxidative metabolism by NADPH-fortified mouse liver micro somes provided an effective route for the oxidation of acetalanthraquinones, producing two polar metabolites for YCG7 and three polar metabolites for both YCG8 and YCG9. The metabolites ofYCG7 and YCG8 were considerably more cytotoxic against the V79 Chinese hamster lung cell line than their respective acetalanthraquinones (4.4-fold for both compounds).YCG9 was found to be relatively cytotoxic per se, possibly due to its different mode of DNA binding, involving 'straddling' of the DNA helix. The increase in cytotoxicity of the metabolized products compared with the acetalanthraquinones supports the concept t?at they were conv.e~ed to their corresponding aldehydes. This leads the way to the deSIgn of acetal-contammg cytotoxic agents which can be selectively activated in tumours.
43
McDonnell, Ursula J. "Synthesis and DNA Binding of Novel Ruthenium Polypyridyl Complexes." Thesis, University of Warwick, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526217.
44
Johnson, Heather Aileen. "Synthesis and evaluation of iminosugars as DNA binding agents." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342492.
45
Isaac, Christian James. "Redox active metal complexes : synthesis and DNA binding studies." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287813.
46
Turlington, Ralph Donald III. "Mitigating security issues in the evolving DNA synthesis industry." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/80897.
Abstract:
Thesis (S.M. in Technology and Policy)--Massachusetts Institute of Technology, Engineering Systems Division, 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (p. 102-108).
DNA synthesis technologies are advancing at exponential rates, with production of ever longer, more complex, and less expensive sequences of double stranded DNA. This has fostered development of industrial scale design, construction, and sale of synthetic DNA. The tools and methods of synthesis used to create beneficial genetic material can also be used to construct dangerous pathogens. To prevent unknown actors from ordering potentially dangerous genetic material, the largest DNA synthesis firms formed two industry associations that require members to screen the DNA sequences ordered and the customers ordering sequences. The firms also worked with the U.S. Health and Human Services to formulate voluntary screening guidelines for synthetic double stranded DNA. As DNA synthesis technology advances and diffuses, this centralized voluntary approach may become less effective. This thesis identifies strengths and weakness in the current voluntary regime and offers recommendations to improve security in the DNA synthesis industry. It describes the origins and current status of DNA synthesis technologies and the structure of the DNA synthesis industry. Then, it describes the formation of voluntary screening consortia and the U.S. and international guidelines that address security issues in DNA synthesis. Finally, this thesis compares DNA synthesis with other potentially "dual use" technologies, concludes that regulatory approaches may not enhance security in this area, and suggests that governments should focus on education and outreach.
by Ralph Donald Turlington III.
S.M.in Technology and Policy
47
Durand, Adeline. "Synthesis of oligonucleotide analogues for use in DNA nanostructures." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/173975/.
Abstract:
Thanks to its ability to form duplexes through selective base-pair recognition, DNA is a unique material for orderly self-assembled construction at the nanoscale. To develop a nanotechnology platform on a grid of addressable molecular building blocks using DNA node structures, DNA complexes need to be fixed onto surfaces. To fulfil this requirement on lipid membranes, phosphoramidites monomers modified with a cholesterol moiety and a spacer unit were synthesised. The hydrophobic spacer provides separation between the hydrophobic cholesterol moiety and the phosphate backbone of the DNA strand. For better anchorage of the network to a lipid surface, a hydrophilic spacer was also used to link the cholesterol to the nucleoside. Solution studies demonstrated that the melting temperature (Tm) of the duplex with adjacent cholesterols on each strand is much higher than that of the unmodified duplex. The reliable and highly selective copper(I)-catalysed azide-alkyne 1,3-dipolar cycloadition (CuAAC), the best known example of click chemistry, has proven to be of remarkably broad utility in synthetic chemistry and in nucleic acid chemistry in particular. CuAAC was exploited for the synthesis of a very stable double stranded catenane duplex. The catenane was formed from a single stranded cyclic template and its linear complement, using a third short oligonucleotide (ODN) as a helper for the circularisation of the second ODN. The copper(I)-catalysed cyclisation of oligonucleotides occurred by reaction between their terminal azide and their opposite terminal alkyne, to produce a 1,2,3-triazole linkage between the two reactants. The catenane was characterised by denaturing polyacrylamide gel electrophoresis, UV melting studies and enzyme digestion.
48
De, Haan Judy Bettina. "DNA synthesis and methylation in normal and transformed cells." Master's thesis, University of Cape Town, 1985. http://hdl.handle.net/11427/27266.
Abstract:
In this study, DNA methylation was examined during the eukaryotic cell cycle, and shown to occur throughout the S phase as well as during the "early" G₂ phase. However, DNA synthesis and methylation of newly synthesized DNA did not occur simultaneously, but the latter lagged behind DNA synthesis by about two hours. Once added during the S phase, the methyl groups were stably maintained in the DNA. Various compounds which are known to affect DNA synthesis in tissue cultured cells, were tested for their ability to alter the methylation status of DNA. The effects of three DNA synthesis inhibitors, viz. hydroxyurea (HU), 1-S-D-arabinofuranosyl cytosine (ara-C) and aphidicolin were examined on a normal embryonic lung fibroblast cell line (WI-38) and its two transformed counterparts, a simian virus 40 (SV 40) transformed line (SVWI-38) and a y-irradiation transformed cell line (CT-1). HU was shown to enhance hypermethylation of pre-existing DNA strands in the normal cells, while ara-C and aphidicolin caused hypermethylation of newly synthesized DNA strands. The effects of various concentrations of a known inducer of gene expression, sodium butyrate, were examined on these three cell lines as well. During a 16-20 hour treatment period, at butyrate concentrations of between 5 and 20 mM, no adverse effect on cell morphology was observed. Cell growth, in the presence of butyrate for 14 hours, showed that butyrate was more toxic on the transformed cells than on the normal cells. However, at 5 mM butyrate, DNA synthesis was inhibited by 75% in the normal cells, and was unaffected in the transformed lines. RNA synthesis was not affected in the transformed cells, whilst in the normal cell line, RNA synthesis was decreased to 76% of the control value, at sodium butyrate concentrations as low as 5 mM. Protein synthesis also was unaffected in the transformed cells and only slightly (+ 10%) inhibited in the normal cells at 20 mM butyrate. SDS polyacrylamide gel electrophoresis of proteins synthesized in the presence of 10 mM sodium butyrate, showed that most proteins were unaffected. Two high molecular weight proteins in the WI-38 cells appeared to be modified during butyrate. treatment, while one protein was induced by butyrate treatment in the CT-1 cells. More importantly though, butyrate treatment also resulted in hypermethylation of DNA, as shown by MSP 1 and Hpa II restriction endonuclease digestion and high-pressure liquid chromatography analysis. Butyrate appeared to specifically cause hypermethylation of pre-existing DNA strands in the WI-38 cells, while the SVWI-38 and CT-1 cells showed preferential hypermethylation of newly synthesized DNA strands. However, the hyper-methylated state was only heritable if the methylation event occurred in newly synthesized DNA. Hypermethylation on pre-existing DNA was rapidly lost in the subsequent generation. It would therefore appear that methylcytosines are only maintained in the DNA if they are generated on newly synthesized DNA. This study has clearly shown that the heritability of DNA methylation patterns is closely linked to DNA replication.
49
Mlodnosky, Karyn L. "Design, synthesis, and screening of small libraries of potential topoisomerase I poisons /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8480.
50
Hilko, David. "Design, Synthesis, and Biological Evaluation of Chemical Probes for Visualising DNA Synthesis in Proliferating Cells." Thesis, Griffith University, 2018. http://hdl.handle.net/10072/384283.
Abstract:
DNA biolabels are chemical probe compounds used detect and visualise DNA synthesis in replicating cells. These compounds are tools that enable biologists to answer fundamental questions regarding the proliferation of cells in diverse fields ranging from developmental biology, infectious disease, and cancer biology.
This thesis describes the design and synthesis of new and synthetically challenging compounds as prospective DNA biolabels. These compounds were then evaluated for DNA biolabelling capacity and cytotoxicity against T. cruzi parasites, the causative agent of Chagas disease.
Chapter One serves as a general introduction and literature review of the history and current state of the art of DNA biolabels, in particular, DNA metabolism of nucleoside analogues and development of new strategies for detection of biolabels incorporated into DNA. This area of research had culminated in the discovery of 5-Ethynyl-2ʹ-deoxyuridine-uridine derivatives for detection and visualisation of DNA synthesis employing click chemistry and fluorescent azides.
Chapter Two describes the design and synthesis of 2ʹ-halo-arabinosyl EdU derivatives as prospective DNA biolabels. This chapter also reviews the state of the art of synthesis of 2ʹ-halo-arabinosyl pyrimidine nucleosides. The synthesis of these new 2ʹ-halo-arabinosyl EdU analogues required a challenging late-stage halogenation strategy. In the development of this strategy, new synthetic methodology evolved employing the unusual N-nitro protecting group. Optimised conditions were developed for quick and gentle installation and removal of the N-nitro protecting group in the presence of sensitive functional groups. Furthermore, the techniques developed for the removal this protecting group allowed for its removal in the presence of functional groups sensitive to reducing conditions.
Chapter Three describes synthesis of cycloSaligenyl 5ʹ-phosphotriester of EdU analogues and a literature review of the synthesis and synthetic strategies used to synthesise cycloSaligenyl phosphotriester of nucleoside analogues. New conditions were explored and developed for the synthesis of the cycloSal phosphotriesters from unprotected nucleoside analogues. These methodologies were successfully applied to multiple nucleoside substrates. A new synthesis and purification of cyclosaligenyl phosphoramidites was developed and successfully applied to four different saligenyl alcohols. This methodology allows for simple and straight forward synthesis of both the cycloSal phosphotriesters and their phosphoramidite precursors.
Chapter Four describes the attempted synthesis of 2ʹ-fluoro-arabinosyl EdU by direct fluorination of the 2ʹ-triflyl precursor and serves to review the particularly difficult synthetic transformation of 2ʹ-fluorination of preformed pyrimidine nucleosides. Towards this end we successfully achieved 2ʹ nucleophilic fluorination of uridine by employing 3-N-nitro stabilised 2ʹ-triflates. This required extensive exploration of conditions and fluoride sources to find appropriate conditions for successful reactions. It was found that basicity of the amine base of the HF-amine complexes was integral to the success of fluorination reactions. Attempts to increase the yields of the fluorination reaction through alternative hydroxyl protecting groups of the uridine-N-nitro-triflate failed. An alternative non-reducing deprotection strategy of the the N-nitro group of the 2ʹ-fluro-3-N-nitro-uridine was developed employing a two-step process. This relied on first forming an N-amino intermediate which was then deaminated to give the free 2ʹ-fluoro-arabinosyl uridine nucleoside. This synthesis afforded 2ʹ-fluoro-arabinosyl uridine in yields 17 times greater than previous reports by direct fluorination of preformed uridine nucleosides.
Chapter Five briefly describes the differences of nucleoside and DNA metabolism of T. cruzi parasite to that of mammalian cells. This chapter also describes the biological evaluation of the EdU and its 2ʹ-halo analogues, and the cycloSal phosphotriester derivatives. The findings revealed that the T. cruzi parasite is extremely sensitive both labelling with EdU and its associated cytotoxicity. Labelling of the parasite with any of the EdU analogues was associated with corresponding cytotoxicity. Improvement of labelling efficiency of some the EdU analogues by functionalisation with cycloSal phosphotriesters demonstrates that thymidine kinase blockade occurs for some nucleoside analogues. Thus the parasite expresses a putative thymidine kinase with restricted substrate specificity comparable to that of higher eukaryotes. The high cytotoxicity of EdU and its analogues may indicate the presence of an alternative cytotoxic pathway not present in mammalian systems, possibly resulting from interference with the base J metabolism.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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