Browsing by Author "Crans, Debbie, advisor"
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Item Open Access Biologically active aromatic acids in phosphatidylcholine liposomes: benzoic and salicylic acids(Colorado State University. Libraries, 2022) Sanders, Sarah Ivy, author; Crans, Debbie, advisor; Van Orden, Alan, committee member; Van Buiten, Charlene, committee memberThe interactions of benzoic acid and salicylic acid with phosphatidylcholine liposomes were characterized to understand interfacial interactions of the two weak aromatic acids with the membrane. The liposomal system was comprised of soy l-ɑ-phosphatidylcholine (SPC) bilayers, which allowed the determination of interfacial interactions and position within the membrane using 1D 1H NMR. Benzoic acid was considered due to its effects as a food stabilizer, where salicylic acid was considered as a derivative due to its effects as an anti-acne agent. Both were found to penetrate the membrane interface deeper when in their protonated forms. The presence of the weak acids on the membrane surface allowed stabilization through hydrogen bonding with liposomal headgroups, which allowed deprotonation to occur. Broadening of aromatic peaks demonstrated a pH dependence for both benzoic acid and salicylic acid, showing a deeper penetration around the pKa values of the weak acids. This study offers justification for the antimicrobial activity of benzoic and salicylic acids in lower pH environments. Thus, this study provides the next piece in understanding the uptake of benzoic acid and salicylic acid in bacteria for microbial inhibition.Item Open Access Characterization of interactions of lipoquinone derivatives within model membrane systems(Colorado State University. Libraries, 2021) Bublitz, Gaia Rachel, author; Crans, Debbie, advisor; Cohen, Robert, advisor; Santangelo, Thomas, committee member; Roess, Deborah, committee memberMenaquinones (MK) are electron carriers composed of a naphthoquinone moiety and an isoprene side chain of variable length and saturation. These molecules are the only quinone derivatives present in the electron transport systems of all Gram-positive bacteria and some Gram-negative anaerobes. Subsequently, MK plays a critical role in respiration for pathogens such as Staphylococcus aureus and Mycobacterium tuberculosis. Although the physiological function and relevance of MK as a redox cofactor have been established, its chemical interactions within the plasma membrane and the effects of these properties on MK-mediated electron transport are still obscure. These unknowns are reflected in existing literature, as MK is commonly depicted in an extended conformation, although in vitro and in vivo studies suggest that biomolecules with alkyl moieties assume folded conformations in native environments (Ko et al., 2011; Trembleau et al., 2003). In this study, we implemented 1D 1H and 2D 1H-1H NMR spectroscopic techniques to characterize the location and 3D conformation of MK-2 within a L-α-phosphatidylcholine liposome model. MK-2, a truncated menaquinone analog, was selected due to its limited rotational variability and previous characterization in a simple monolayer lipid system (Koehn et al., 2018). Our data suggests that MK-2 is largely incorporated into the phospholipid bilayer, with an aqueous subspecies residing at the polar membrane interface in a concentration-dependent manner. 2D NOESY spectroscopic analysis supports the interpretation that both the aqueous form and the membrane-associated form of MK-2 assume a folded conformation. These findings provide a reference for the study of the properties of MK derivatives with longer isoprene chains, which are analogous to functional MK variants in native environments.Item Open Access Fundamental studies of reverse micellear aggreagates by multinuclear and multidimensional NMR spectroscopy(Colorado State University. Libraries, 2012) Sedgwick, Myles, author; Levinger, Nancy, advisor; Crans, Debbie, advisor; Henry, Chuck, committee member; Roess, Deborah, committee member; Van Orden, Alan, committee memberSelf-assembled reverse micellar aggregates using cationic, anionic and non-ionic surfactants have been investigated by multinuclear and multidimensional NMR. By utilizing 51V NMR chemical shifts and line widths of decavanadate, the local proton concentration and characteristics of the reverse micellar environment are measured. There is a distinct environmental change on the interior of the reverse micelle depending on the surfactant used. 51V NMR signals for decavanadate inside an Igepal CO-520, non-ionic surfactant, reverse micelle display sharp signals indicating the decavanadate experiences water like environment. Conversely, 51V NMR signals for decavanadate inside an Igepal CO-610/430 mixed reverse micelle show significant broadening of the decavanadate signal indicating that the environment inside the reverse micelle in which the decavanadate resides is more viscous. These data provide a description in that the water pool of non-ionic surfactants can be compared. Time resolved anisotropy decays, ultrafast time-resolved transient absorption, and 2D NMR spectroscopy have been used to study proton transfer reactions in the interiors of Igepal-CO 520, CTAB and AOT reverse micelles. For ѡ0 = 10 reverse micelles formed with anionic AOT surfactant, the HPTS proton transfer dynamics are similar to dynamics in bulk aqueous solution, and the corresponding 1H 2D NOESY NMR spectra display no cross peaks between HPTS and AOT consistent with the HPTS residing, well-hydrated by water, in the interior of the reverse micelle water pool. In contrast, ultrafast transient absorption experiments show no evidence for HPTS photoinduced proton transfer reaction in reverse micelles formed with the cationic CTAB surfactant. In CTAB reverse micelles, clear cross peaks between HPTS and CTAB in the 2D NMR spectra show that HPTS embeds in the interface. Similar behavior is observed for HPTS in Igepal reverse micelles as in CTAB reverse micelles and we interpret the slowed dynamics in the same manner. The 2D NMR spectra for HPTS in Igepal-CO 520 reverse micelles shows interaction that imply the HPTS molecule is rested near the interface inside the reverse micelle. Dynamic light scattering (DLS) and 1H NMR spectroscopic experiments suggest that the assembly of the reverse micellar aggregates depends on non-polar solvent and co-surfactant used. Two different self-assembled particles form in the AOT/cholesterol /water in cyclohexane, where in the similar system of AOT/cholesterol /water in 1-octanol there is only one particle present. In microemulsions employing 1-octanol as the continuous medium, AOT reverse micelles form in a dispersed solution of cholesterol in 1-octanol. Although the size distribution of self-assembled particles is well-known for many different systems, evidence for simultaneous formation of two distinctly sized particles in solution that are chemically different is unprecedented. By utilizing optical spectroscopic techniques, 2D NMR, and DLS, the structure of the non-ionic reverse micelles have been characterized. The impact of adding cholesterol, a biologically relevant molecule, has on the structure of the reverse micellar solutions has also been shown.Item Embargo NMR thermometry of vanadium based ligand-to-metal-charge transfer complexes(Colorado State University. Libraries, 2023) Grundy, Josef, author; Zadrozny, Joe, advisor; Crans, Debbie, advisor; Wu, Mingzhong, committee memberMagnetic resonance imaging (MRI) is a noninvasive imaging technique that utilizes safe, nonionizing radiation for the diagnosis of early-stage diseases, including cancer. Although this technique provides a wealth of anatomical information, there are limitations in the information that MRI provides, such as the accurate local temperature in specific parts of the body. 51V is a promising candidate for a high-resolution NMR thermometer due to its intrinsically low quadrupolar moment and subsequent narrow linewidth. Unlike other nuclei, such as 59Co, design strategies for increasing the temperature sensitivity of 51V complexes are currently unexplored. We present a route of amplifying temperature sensitivity of the 51V chemical shift via ligand-to-metal charge transfer electronic structure design criteria. We demonstrate that this design strategy can boost the temperature dependence of the 51V chemical shift by an order of magnitude.Item Embargo Synthesis and characterization of biologically relevant redox-active molecules(Colorado State University. Libraries, 2023) Kostenkova, Kateryna, author; Crans, Debbie, advisor; Zadrozny, Joseph, committee member; Paton, Robert, committee member; Worley, Deanna, committee memberRedox chemistry is fundamental to several essential life processes, such as energy metabolism, respiration, and free radical formation. Many redox-active inorganic and organic molecules are promising agents to combat difficult-to-treat diseases, including cancer and tuberculosis. This dissertation covers the syntheses, studies of the fundamental chemical and biological properties of two vastly different classes of redox-active molecules, inorganic and organic molecules. Most of this work has investigated the fundamental development of hydrophilic, hydrophobic and amphiphilic redox-active vanadium complexes for the treatment of different types of cancer. The last chapter of this dissertation describes the studies of the fundamental properties of demethylmenaquinones which are biosynthetic precursors to menaquinones, lipid electron carriers essential for anaerobic bacterial respiration of several types of bacteria, including Escherichia coli, Actinomadura madurae and pathogenic Mycobacterium tuberculosis. Targeting bacterial electron transport chain disrupts respiration of pathogenic Mycobacterium tuberculosis, thus, studying the properties of demethylmenaquinone analogs is of great interest. Chapter one, an introductory chapter, presents a comprehensive review of the developments in vanadium anticancer therapeutics over the last five years. The structural diversity of the vanadium-containing anticancer compounds, potential applications to various cancer cell lines, and different modes of delivery of highly cytotoxic vanadium species are described in detail. Vanadium gained interest for its anticancer applications after bis(maltolato)oxovanadium(IV), an antidiabetic complexes studied in Phase II clinical trials, went off patent in September 2011. Previous studies with vanadium antidiabetic complexes, however, provided valuable information to understand the action of novel vanadium anticancer complexes, as cancer and diabetes target the same metabolic pathways. Chapters two and three describe the syntheses, spectroscopic characterization, and cytotoxic studies of novel vanadium(V) catecholate complexes with pyridine-containing Schiff base ligands. According to previous reports, vanadium(V) Schiff base catecholate complexes are promising agents for glioblastoma treatment, and herein we investigated whether the presence of the pyridine ring on the Schiff base scaffold improves cytotoxicity and hydrolytic stability of the vanadium catecholato complexes. The studies showed that the presence of the pyridine ring improves hydrolytic stability of the V(V) catecholate complexes, yet it decreases their uptake into glioblastoma cells which result in the decrease of cytotoxicity of the complexes. Even though the stability increased and the compounds have enough time to get into cells, the efficacy of these complexes decreased. Chapter three further explores the redox properties and the redox reaction mechanism of vanadium(V) Schiff base catecholate complexes with pyridine-scaffolds and tert- butyl substituted catecholate ligands. Chapter four describes the speciation studies and testing of vanadium(V) dipicolinate that enhance the effects of oncolytic viruses, non-pathogenic viruses that can infect and kill cancer cells. Additionally, the chapter describes 1H and 51V NMR studies carried out in model membrane interfaces. The data show that V(V) dipicolinates hydrolyze under physiological conditions and generate vanadate which ultimately enhances the spread of the oncolytic viruses. V(V) dipicolinates are located on the interface of the aqueous pool and hydrophobic region of model membranes which also contributes to their hydrolysis. Chapter five describes PtIV and MoVI monosubstituted decavanadates, monoplatino(IV)nonavanadate(V) ([H2PtIVVV9O28]5-, V9Pt), and monomolybdo(VI)-nonavanadate(V) ([MoVIVV9O28]5-, V9Mo), and their ability to initiate signal transduction on the luteinizing hormone receptor (LHR) in CHO cells and their speciation chemistry under the biological experiments. The PtIV and MoVI monosubstituted decavanadates are large vanadium- oxo clusters that are structurally similar to decavanadate but have different charges. The results showed that both V9Mo and V9Pt affect LHR expression and do not inhibit cell growth which is different than the decavanadate ([V10O28]6−, abbreviated V10). Although all the clusters hydrolyze under the assay conditions lifetimes are different, and this was characterized using spectroscopic methods. Using the washing experiments, we were able to show that the V9Pt and V9Mo monosubstituted decavanadates do not associate with the cells and, hence, do not negatively affect cell growth, however, they are more effective in initiating signaling. Chapter six describes initial efforts to study the fundamental properties of two truncated demethylmenaquinones, biosynthetic precursors for menaquinones. The studies are important to understand the fundamental differences between the chemical properties of menaquinones and demethylmenaquines which include 3D conformation and redox potential. Indeed, the development of inhibitors of MenG, a methyltransferase enzyme that coverts demethylmenaquines to form menaquinones, is a known target for drug development for antitubercular applications. Therefore, we investigated whether non-native demethylmenaquines would convert to menaquinones by the relevant enzymes present in the membrane preparations. In summary, the first five chapters demonstrate 1) the diversity of applications of vanadium compounds for treatment of different types of cancer and 2) the efforts to develop vanadium- based anticancer therapeutics to treat different types of cancer. The final chapter describes efforts in fundamental studies preparing and characterizing the chemical properties the truncated demethylmenaquinones. In addition, we demonstrated that the membrane preparations of mycobacteria concerted the synthesized truncated demethylmenaquinone-2 and demethylmenaquinone-3 are processed to form menquinone-2 and menaquinone-3.Item Open Access The use of model membrane techniques for the analysis of interactions, conformation and redox properties of menaquinones and other small molecules(Colorado State University. Libraries, 2021) Doucette, Kaitlin A., author; Crans, Debbie, advisor; Crick, Dean, committee member; Roess, Deborah, committee member; Menoni, Carmen, committee memberThis thesis explores the use of model membranes to solve complex problems in determining the placement, conformation, and electrochemical properties of hydrophobic compounds as they interact with a model membrane. Menaquinone, an electron transporter commonly found in Gram-positive and Gram-negative obligate anaerobes, consists of a naphthoquinone head group and isoprene tail of variable length and saturation. Chapter two shows the use of liposomal model membranes to solubilize menaquinone analogues of variable length and saturation for aqueous electrochemical studies characterizing half-wave potentials, reversibility, and diffusion coefficients to examine its redox properties in connection to its role as an electron transporter. This work shows a distinct odd-even effect with respect to the isoprene chain length of the compound and its electrochemical properties. The exploration of this project is continued in chapter three, in which the conformation and placement of menaquinone-2 is determined in the context of a phosphatidylcholine liposome using 1D and 2D 1H NMR. Finally, chapter four explores the use of a reverse micellar model membrane for determining the placement of glycine and short glycine peptides to explore its placement near a membrane with regards to its role as a neurotransmitter and to explore its potential role in antimicrobial peptides. The experiments contained herein show that model membranes are a useful tool for the study of hydrophobic compounds and molecules commonly found within a cellular membrane.