Browsing by Subject "Bioinorganic"

Now showing 1 - 4 of 4
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    The Chemistry of S = 2 Nonheme Oxoiron(IV) Complexes
    (2016-05) Puri, Mayank
    Nonheme oxoiron(IV) intermediates are proposed to be involved in a number of important biological oxidation reactions, where all characterized examples thus far have a S = 2 ground spin state. In contrast, the majority of synthetic nonheme oxoiron(IV) complexes have a S = 1 ground spin state. In order to gain a deeper understanding of these important biological species, it is critical to expand the number of synthetic S = 2 nonheme oxoiron(IV) complexes and to study their reactivity with organic substrates. This thesis explores a synthetic strategy to obtain S = 2 nonheme oxoiron(IV) complexes by utilizing weak-field equatorial quinoline donors, in contrast to the relatively strong-field pyridine donors that are often used. The resulting S = 2 nonheme oxoiron(IV) complexes demonstrate spectroscopic signatures similar to those of the enzymatic oxoiron(IV) intermediates and reproduce the reactivity observed by these nonheme iron enzymes. Thus, this research has given rise to the first electronic and functional models of the nonheme oxoiron(IV) intermediates found in the enzymes TauD, CytC3 and SyrB2. In addition, the reactivity of known S = 1 nonheme oxoiron(IV) complexes were explored in the context of oxygen-atom exchange with H2O, which is an important reaction in tracking metal-oxo intermediates proposed to be involved in catalytic substrate oxidation reactions. Finally, a six-coordinate S = 1 nonheme imidoiron(IV) complex supported by a tetradentate ligand was synthesized and compared to its isoelectronic S = 1 nonheme oxoiron(IV) analogue.
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    Method Development and Degradation Studies to Verify the Stabilization of a Gallium Prodrug of Epinephrine
    (2021-09) Livezey, Nicholas
    Utilizing the unique and varied properties of metals, such as their redox activity, lability, and net charge, metal-based prodrugs can be designed and optimized for numerous applications. The most prominent usage of metal-based prodrugs has historically been anti-cancer agents, though there have been more recent efforts in the development of theranostic and antimicrobial agents as well. Gallium has promise for extending the scope of metal-based prodrugs, as it has been FDA approved for the treatment of tumors and hypercalcemia. Epinephrine is a compelling target for a gallium-based prodrug as conventional prodrugs are not suitable for the treatment of anaphylactic shock. This is because the prodrugs are inactive during their long half-lives. Additionally, as should mitigate drug degradation from high pH, light, and heat. The development of a novel gallium prodrug of epinephrine establishes the first prodrug treatment of anaphylactic shock, and extends the chemical space of metal-based prodrugs.
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    Mono- and Dinuclear Nonheme Iron Model Complexes: O-O Bond Activation, Structural Characterization and Reactivity Study
    (2015-05) Rohde, Gregory
    The structures and reactivities of mono- and dinuclear nonheme iron model complexes were investigated. In Chapters 2 and 3, O-O bond activation of H2O2 by the dinuclear complexes [(FeIII2(μ-O)(μ-OH)L2]3+ (1A) and [(FeIII2(μ-OH)2L2]4+ (2A), L = tris(3,5-di-methyl-4-methoxypyridyl-2-methyl)amine, to form the high-valent [(FeIV2(μ-O)(OH)(O)L2]3+ (3A) and [(FeIV2(μ-O)2L2]4+ (4A) was studied. H2O2 and H2O competed for binding to the Fe centers of 1A and 2A, and [H2O2] was rate limiting under the concentrations studied. The presence of base increased the H2O2 activation rate for 2A, but not for 1A. The H2O2 activation rates by 1A and 2A were comparable to that of the mononuclear nonheme iron complex [FeII(TMC)]2+ (TMC = tetramethylcyclam) (J. Am. Chem. Soc. 2010, 2134-2135) after accounting for water inhibition. A crystal structure of [(FeIV2(μ-O)2L2]4+ (4A), or diamond core, was solved and described the Fe2O2 core in more detail than the original EXAFS structural assignment. In addition, structures of other complexes with Fe2O2L2 cores in different oxidation and protonation states were also studied and compared to the Fe2O2 cores of the high-valent enzymes intermediates RNR-X and sMMO-Q. In Chapter 4, iron complexes supported by the TMC ligand were studied by X-ray crystallography. A second isomer of the [FeIV(O)(TMC)]2+ complex was found, and the mechanism of conversion to the original isomer was explored. Additionally, the crystal structure of (TMC)FeIII(μ-O)Sc(NCCH3)(OTf)4 complex was obtained and used to reassign the Fe oxidation state of the originally reported (TMC)FeIV(μ-O)Sc(OH)(OTf)4 complex.(Nat. Chem. 2010, 756-759) In Chapter 5, the hydrogen atom transfer (HAT) rates of a series of S = 2 mononuclear nonheme iron complexes, [FeIV(O)TMG2dien(X)]2+,+ (X = CH3CN, Cl-, Br-, N3-, CH3CO2- and CF3CO2-; TMG2dien = 1,1-bis{2-[N2-(1,1,3,3- tetramethylguanidino)]ethyl}amine), were reported. Substitution of CH3CN with carboxylate and halide anions cis to the oxo ligand increased the HAT oxidation rate by as much as 15 times. A series of S = 1 nonheme iron complexes, [FeIV(O)TPA(Y)]2+,+ (Y = CH3CN, Cl-, CH3CO2- and CF3CO2-; TPA = tris(pyridyl-2-methyl)amine), was also investigated to explore what effect spin state has on reactivity. The HAT rates were similar for the [FeIV(O)TPA(Y)]2+,+ series, while OAT rates were much faster for the [FeIV(O)TPA(CH3CN)]2+ species.
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    Optimizing Metal Complexes as Bacteria-Specific Tracers for in vivo Nuclear Molecular Imaging and Modulators of the Nuclease Resistance of DNA Nanostructures
    (2023-05) Joaqui Joaqui, Michel Andrey
    Infectious diseases caused by bacteria remain one of the major global threats to human health. Rapid and precise diagnosis is thus crucial for preventing the propagation of these bacterial pathogens and achieving favorable treatment results for impacted patients. To achieve this, diagnostic methods must possess the ability to accurately detect the bacterial pathogen with high selectivity, while also being prompt to facilitate rapid containment and informed treatment decisions. In vivo nuclear molecular imaging modalities such as PET and SPECT have gained importance as alternative diagnostics techniques, especially in scenarios where the site of infection is unknown, or the extraction of sample is anatomically challenging rendering well-established in vitro diagnostic techniques impractical. The effectiveness of these in vivo imaging techniques heavily relies on the utilization of proper radiolabeled probes that target bacteria. Currently, there are no radiotracers available that can be swiftly and easily prepared and that exhibit the necessary selectivity for bacterial cells to enable clear and definitive diagnosis. The first part of this dissertation presents an investigation regarding the use of artificial siderophore analogs of enterobactin, a bacterial virulence factor, as promising scaffolds for the development of metal-based radiopharmaceutical agents suitable for the detection of bacteria in vivo. The study covers the rationale behind the design of the artificial enterobactin analogs, the study of the in vitro and in vivo stability of the 68Ga and 45Ti-labeled enterobactin analogs, their suitability as nuclear imaging agents, as well as the evaluation of their abilities to image a bacterial infection in vivo.The second part of this dissertation, on the other hand, is dedicated to exploring the stability challenges faced by DNA nanotechnology in biologically relevant environments, particularly the instability of DNA-based nanomaterials. DNA nanostructures exhibit unique properties and hold great potential in areas such as biotechnology, nanoelectronics, and nanomedicine. However, these materials encounter numerous hurdles, such as degradation by nucleases and enzymes when introduced into biological environments like blood, tissues, or cells. Such degradation significantly impairs the stability and performance of DNA nanomaterials, curtailing their effectiveness in biological and biomedical applications. Hence, the field of DNA nanotechnology is currently grappling with the critical challenge of devising techniques to enhance the stability and performance of DNA nanomaterials under such conditions. The second section of this dissertation describes a methodical exploration of the modulation of the degradation of DNA nanocages through reversible supramolecular functionalization with metal complexes. The study encompasses the development and synthesis of several coordination compounds featuring metal centers such as EuIII, TbIII, PtII, CuII, CoII, and RuII, as well as a diversity of ligands. Further, the binding affinities of these metal complexes for DNA nanostructures are assessed, and their ability to mitigate the degradation of DNA nanostructures in biologically relevant media is evaluated.