Oxidative damage to DNA is implicated in mutation, premature aging and disease. At the molecular level, the primary process is one-electron oxidation of one of the nucleobases to form a radical cation. Despite the fundamental importance of the nucleobase radical cations, most of what is known about their production and reactions in duplex DNA has come from indirect experimentation. Specifically, direct spectroscopic studies have proved difficult due to small signal sizes, interfering absorptions from reaction initiators, and low time-resolution in existing methodology. This thesis describes a novel approach to the study of the radical cations of the DNA nucleobases. Several novel photochemical sensitizers have been developed that allow these species to be formed with high efficiency, with high time-resolution, and with minimal interference in spectroscopic experiments. This approach has allowed the reactions and properties of the nucleobase radical cations to be studied both in buffered water and in duplex DNA. The kinetics of electron and proton transfer reactions of the purine radical cations are described for the first time. The thermodynamics of these electron and proton transfer reactions have also been determined using novel kinetic methods. Studies in duplex DNA have shown that rapid deprotonation of the guanine radical cation occurs, shifting the location of the positive charge from guanine to cytosine, which has significant implications for the mechanisms of long-range charge transport and formation of DNA oxidation products. Experiments in DNA with multiple G sequences suggest that deprotonation can be inhibited due to charge delocalization. Experiments in DNA with adenines and thyrnines allow observation of both purine and pyrimidine oxidation intermediates. Spectroscopic evidence for formation of delocalized radical cations is obtained for DNA containing multiple A sequences. These experiments represent the first direct spectroscopic studies of DNA oxidation.

Fluorescent labeling of biological materials using small organic dyes is widely employed in the life sciences and have been used in a variety of applications that include diagnostics and imaging. Quantum dots have the potential to overcome problems encountered by organic molecules and have been exploited for applications in biological imaging4 and in single particle tracking studies. The dithiolane ring can be exploited to attach a diversity of organic compounds to CdSe-ZnS core-shell nanoparticles. The introduction of spectroscopic labels as transazobenzene chromophores offers the opportunity to quantify the average number of dithiolane anchoring groups attached to each quantum dot. The transition from monomeric ligands with a single dithiolane anchor to polymeric ligands with multiple dithiolane anchoring groups can be exploited to raise the number of chromophoric labels adsorbed on each quantum dot. Systems showing FRET have been developed on the basis of supramolecular association of BODIPY based dyes or quantum dots as donors and organic chromophores as acceptors. Amino-terminated dyes and quantum dots associate with the chromophores through an ammonium moiety on addition of acid, thereby bringing them closer. Addition of base increases back the fluorescence intensity of the donor completely because of the dissociation. However a similar system with quantum dots as donor, show a very small restoration of fluorescence possibly due to non-specific interaction. In the next project, introduction of spectroscopic labels, in the form of BODIPY dye within the ligands offered the opportunity to quantify the average number of dithiolane anchoring groups attached to each quantum dot. Both fluorescence resonance energy transfer and electron transfer mechanisms are responsible for the quenching of quantum dot fluorescence and unfortunately does not make the system suitable for pH sensing. In the final project, BODIPY-oxazine based fluorophore-photochrome dyad has been assembled by a connecting triazole ring, such that the emission of the former can be modulated by the electronic and structural changes caused by the photoinduced transformations of the later. Further experiments need to be conducted on the fluorophore-photochrome dyads to switch the luminescence of the former with optical inputs.

The first part of this dissertation focuses on the kinetic aspects of atom transfer radical addition ATRA) in the presence of reducing agents. The rate of alkene consumption was found to be dependent on the initial concentration of the radical initiator and its decomposition and termination rate constants but not on the concentrations of CuI and CuII, which was contrary to the rate law for copper-catalyzed ATRA in the absence of a reducing agent. Kinetic experiments showed that the observed rate of ATRA kobs) was indeed not dependent on the concentration of the catalyst, which supported the newly derived rate law. However, product selectivity was highly dependent on the nature of the catalyst. The activation ka,AIBN) and deactivation kd,AIBN) rate constants of various CuII/AIBN systems were determined through a combination of experimental and theoretical methods and were found to control the overall concentrations of CuI and Cu II at equilibrium. The effect of the catalyst, alkyl halide, and free radical initiator concentrations on the percent conversion and yield of monoadduct were also investigated. Lower catalyst loadings in ATRA reactions involving reactive monomers led to a decrease in monoadduct yield due to competing polymerization reactions. Low-temperature ATRA reactions were found to significantly increase the formation of the monoadduct as a result of the lowering of the rate constant of propagation kp). Reactions of less active halides were more affected by increased alkyl halide concentrations than that of the more active alkyl halides. Higher free radical initiator concentration led to an increase in AIBN-initiated polymer formation. The second part explores the role of thermodynamic factors on the product selectivity of atom transfer radical cyclization ATRC). Various derivatives of alkenyl bromoacetate and trichloroacetate were synthesized and characterized by 1H NMR spectroscopy. Theoretical calculation of the relative energies of the s-trans and s-cis conformers revealed that the presence of bulky substituents on the carbon atom alpha to the acetate moiety stabilizes the s-cis conformation and, thus, promotes cyclization. This was experimentally confirmed in the ATRC reactions of the synthesized alkenyl haloacetates in which the addition of bulky groups increased the yields of cyclic products.

The work reported in this dissertation focuses on synthetic ion transporters SATs). SATs have a relatively simple chemical structure but they aggregate, self-assemble and insert in biological membranes much in the same way as their much more complex naturally occurring analogs. This makes SATs valuable tools for the investigation of these supramolecular and membrane related processes with the final goal of developing new therapeutical agents useful in the treatment of conditions stemming from ionic imbalances. Two families of synthetic anion transporters are studied in this dissertation: pyrogallol[4]arene derivatives and dianilides of isophthalic and dipicolininc acids. Experiments aimed at investigating their solution behavior, anion binding properties and the strength of the interactions present in the host&bull；anion adducts employed analytical techniques such as high performance liquid chromatography, electrospray mass spectrometry, UV-vis and NMR spectroscopy. Insights derived from these experiments were instrumental to our understanding of the stability and transport mechanisms pertaining to these two families of compounds.

In support of the recent interest in fuels from renewable resources for fuel cells, the intermediates of the oxidation of formic acid and ethanol to CO2 on platinum electrodes have been examined. The adsorbed carbon monoxide intermediate continues to be the cause for a decrease in efficiency and activity for platinum electrodes and is the leading surface poison intermediate) in the most common oxidation reactions. We have studied the CO species generated from both fuel and CO-saturated media to observe site conversion of the CO species on polycrystalline platinum and platinum single crystal surfaces with respect to concentration, composition of electrolyte, and potential with electrochemical techniques and broad-band sum frequency generation spectroscopy BB-SFG). In situ BB-SFG allows for the chemical analysis of electrode surfaces to examine details of surface electrochemical reactions. SFG is based on a second order nonlinear optical process that is forbidden in centrosymmetric media. Therefore, SFG is intrinsically interface-sensitive and enables surface chemical measurements without contribution from the bulk. With the aid of a femtosecond IR laser, we probe vibrational transitions of adsorbates in real time on the electrode surface as the potential at the surface is scanned at rates up to 5 mV/s. Studies of CO species, other reaction intermediates, and adsorbates will be discussed in relation to their poisoning of catalysis by single crystal Pt electrodes. These experiments demonstrate the sensitivity of the BB-SFG technique to the adsorbed species, and its capability to examine adsorption site conversions of the species on the electrode surface. In formic acid fuel solution, in situ BB-SFG was used to obtain vibrational spectra of CO adsorbates produced from formic acid oxidation on a Pt100) electrode in sulfuric acid and perchloric acid media. The BB-SFG simultaneously monitored all forms of the CO intermediates, including steady-state, as the potential was scanned at 5 mV/s. Spectra were compared to those obtained from CO adsorbed from a CO-saturated electrolyte. While adsorbed from HCOOH, CO had a sharp atop transition near 2050 cm-1 and a broader multiply-bonded transitions in the 1700–1900 cm-1 range, which appear to result from bridge-like and higher-coordinated possibly fourfold) CO. As the potential was scanned from -0.2 to 0.3 V vs. Ag/AgCl), the bridge-like CO disappeared and the amount of atop CO increased. At potentials above 0.5 V, CO was in steady-state, being oxidized on the surface to CO 2 and replenished by CO from HCOOH. These measurements show that BB-SFG can observe potential-dependent interconversion of different CO forms on the electrode surface and can measure steady-state reaction intermediates on a surface in real time. In situ BB-SFG was also employed to study ethanol on platinum electrodes as a means to elucidate the mechanism of this reaction on catalyst surfaces for fuel cell applications. Recently, the interest in ethanol has increased, not only as a renewable resource, but especially as a fuel source due to its high theoretical yield of 12 electrons released upon complete oxidation. Incomplete oxidation, a major setback with ethanol oxidation, forms byproducts and intermediates slowing the oxidation reaction or prohibiting it from occurring further. Among the byproducts are acetic acid and acetaldehyde, where the C-C bond is not yet broken, or the intermediate CO, where the C-C bond has been broken and is further oxidized to CO2. Using simultaneous electrochemical techniques and broad-band sum frequency generation, these byproducts and intermediates formed on platinum electrodes will be discussed in both acidic and basic media, as a function of electrolyte composition and ethanol concentration.

A set of three through-bond energy transfer cassettes based on BODIPY as a donor and cyanine dyes as acceptors has been prepared via Sonogashira couplings, and their photophysical properties were examined. These cassettes fluoresce around 600 to 800 nm and are resolved by approximately 100 nm. This property is an important factor for multiplexing study in cellular imaging. Several useful fluorescent probes such as 5- and 6-carboxyfluorescein, water-soluble BODIPY, and water-soluble Nile Blue dyes, have also been synthesized and their photophysical properties studied. We have also attempted to develop a method for protein mono-labeling via a solid-phase approach. The labeling of protein with one fluorescent dye facilitates quantification and single molecule imaging in biological applications. Various solid-supports such as PEGA, CPG, and BSA-coated CPG, were tested. Photolabile and chemically cleavable linkers were prepared to connect solid-supports and fluorophores. Unfortunately, our approach to the fluorescent mono-labeling of native proteins did not give us any conclusive results.

Supramolecular architectures composed of multiple components are challenging to produce, as the enthalpic gain must be greater than the entropic penalty of strict geometrical arrangements. Therefore, it is the goal of supramolecular chemists to strategically design and synthesize molecules that will exhibit selectivity toward formation of a particular complex. This dissertation describes the formation of supramolecular architectures of increasing size and is organized in the following way. Chapter 1 introduces the reader to the field of supramolecular polymer chemistry. Chapter 2 describes the synthesis of a series of monovalent ditopic guests II-1–II-6) and their complexation properties toward double cavity cucurbituril host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather than the desired n:n supramolecular polymers. Guest II-7 which contains a longer biphenyl spacer successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex bis-ns-CB[10]2 &middot；II-72) rather than supramolecular polymer. Guest II-8 is heterovalent and ditopic and is shown to reversibly form 2:2 and 1:2 complexes bis-ns-CB[10]2&middot； II-82 and bis-ns-CB[10]&middot；II-8 2) in response to changes in host:guest stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6] which selectively targets the hexanediammonium ion binding region of II-8 and delivers the penta-molecular complex bis-ns-CB[10]&middot； II-82&middot；CB[6]2. Chapter 3 describes the formation of a main chain supramolecular polymer from a mixture of polydiallyldimethylammonium chloride) III-1) and bis-ns-CB[10]. The bis-ns-CB[10] molecular container behaves as a molecular handcuff, bringing together two ends of individual polymers to form III-1n&middot； bis- ns-CB[10]m, resulting in an extension of the length of polymer. The effect of bis-ns-CB[10] on the physical properties of the polymer was investigated using viscometry in aqueous solution. A decrease in the etarel was observed upon increasing concentrations of bis-ns-CB[10] to a solution of III-1. Atomic force microscopy AFM), and diffusion-ordered spectroscopy DOSY) were performed to probe the mode of interaction between polymer III-1 and bis- ns-CB[10]. Collectively, the data supports the two roles for bis- ns-CB[10]: 1) as a deaggregation agent, and 2) as a molecular handcuff that non-covalently links individual polymer strands resulting in overall extension of the polymer.

Platensimycin and Platencin are two novel and closely related antibacterial natural products. Both compounds can inhibit bacterial cellular lipid biosynthesis and exhibited potent inhibitory activity against a broad range of antibiotic-resistant strains. We have accomplished an enantioselective total synthesis of platensimycin as it is described in Chapter 1. This chiral pool-based synthesis starts from the commercially available natural product ＋)-carvone, which determines the stereochemistry of the final product. An asymmetric Horner-Wadsworth-Emmons reaction successfully set up the critical trisubstituted E -olefin. The key step was an innovative intramolecular Diels-Alder reaction, which provided the complex oxatetracyclic core together with four stereocenters, including two quaternary chiral centers present in the molecule, in a single step operation. Chapter 2 described our formal total synthesis of platencin. This concise synthesis utilized only nine steps starting from a commercially available material with 11% overall yield, featuring a Michael cyclization to produce a symmetric diketone key intermediate and a radical cyclization to provide the complex core structure. My thesis work also involved the design and synthesis of severe acute respiratory syndrome SARS) coronavirus CoV) chymotrypsin-like protease 3CLpro) inhibitors. SARS is a fatal respiratory illness and there exists no effective therapy. SARS-CoV 3CLpro plays an important role in the life cycle of SARS-CoV and is an attractive target for anti-SARS drug development. Two sets of inhibitors were developed based on the lead compound AG7088. These inhibitors exhibited potent antiviral activity against SARS-CoV, in infected cells, in the micromolar range. Two crystal structures of inhibitors bound to SARS-CoV 3CLpro were successfully determined. All the synthesized inhibitors share the same lactam P1-ligand that was stereoselectively synthesized by utilizing 1,3-asymmetric induction by a dianionic alkylation protocol. The modified P2-ligands were installed using asymmetric alkylation of a lactone precursor, which possessed the required P3-ligand.

New (＋)-discodermolide analogs were designed by Professor Mark A. Lipton using FEP calculations to simulate the interactions of the analogs with (＋)-discodermolide biological target, beta-tubulin. i-Pr Analogs at C12 and/or C20 showed higher affinity to beta-tubulin compared to (＋)-discodermolide. Progress in the synthesis of hyperdermolides 1.12, 1.13 and 1.14, analogs of the anti cancer agent (＋)-discodermolide at C12 and C20, is described. Starting from enantiopure epoxy vinyl sulfone 1.18, whose preparation was optimized via a novel Jacobsen protocol, vinyl sulfone chemistry was employed to synthesize diastereomerically pure dipropionate units leading to (＋)-discodermolide fragments and analogs. Ozonolysis of vinyl sulfones/phosphonates was also explored and provided termini differentiated C1-C7, C9-C13 and C15-C24 fragments and analogs of (＋)-discodermolide. Completion of the synthesis of the desired fragments and their analogs was accomplished on a gram scale and couplings will be performed in the near future.

In this study a scheme for the selective immobilization of silica nanoparticles on silicon surfaces was developed. The particular methodology explored takes advantage of the broad diversity of chemical moieties afforded by the introduction of polymer brushes grafted from the nanoparticle surface. The functional groups in the polymer brush function as half of a chemical linker, while small molecules bound to the silicon surface via self assembled monolayers serve as the complimentary portion of the linkage system. Several monomers were synthesized for use in ATRP or RAFT polymerizations from the surface of the silica nanoparticles. The resulting polymer encapsulated nanoparticles were immobilized on prepared silicon surfaces and the surface densities of the various immobilized nanoparticles were compared using atomic force microscopy. Nanoparticles encapsulated using ATRP were found to result in significantly lower nanoparticle surface densities than those prepared using RAFT polymerizations. Additionally, methodologies for nanoparticle immobilization were compared, with the most effective technique being the evaporative deposition of the nanoparticles from a dilute suspension. The final portion of the study demonstrated how the immobilization system could be used to create more complex nanoarchitectures via layer by layer assembly techniques.