Browsing by Author "Binghe Wang, Committee Chair"

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    Development of Boronic Acid-Based Spectroscopic Sensors for Saccharides
    (2004-01-06) Ni, Weijuan; Suzanne T. Purrington, Committee Member; Stefan Franzen, Committee Member; Binghe Wang, Committee Chair; Daniel L. Comins, Committee Member
    Boronic acid functional group is used widely as a recognition moiety for the development of sensors for saccharides, due to its unique strong and reversible interaction with diols. The fluorescence and/or UV spectroscopic method are the easiest and most common methods to signal the binding event of these receptors (boronic acid compounds) with saccharides. This dissertation consists of three major parts. First, a series of fluorescent diboronic acid compounds with an anthracene PET (photoinduced electron transfer) system were designed and synthesized (Chapter 1). These compounds can be used as sensors for cell surface carbohydrates, such as sialyl Lewis X (sLex), which are known to be biomarkers for certain cancers. Among these diboronic acid compounds, the lead compound was found to fluorescently label cells expressing sLex selectively. The structure of the lead compound was modified and new conformationally constrained analogs were synthesized. Second, the mechanism of the fluorescent photoinduced electron transfer (PET) system, which was used in our design of fluorescent sensors for sLex, was examined in detail using both density functional calculation (DFT) and model compound fluorescence studies. Based on the study, a new hydrolysis mechanism was proposed (Chapter 2 and 3). Third, novel nitrophenol-based boronic acid reporter compounds, which show significant UV spectroscopic changes upon addition of sugars at neutral pH in aqueous solution, were designed and synthesized (Chapter 4). The design took advantage of the ability of a boronic acid functional group to modulate the pKa and/or the electron density of a neighboring group. These reporter compounds can be used as the recognition and signaling unit for the construction of polyboronic acid sensors for selective and specific recognitions of saccharides of biological significance.
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    (I) Development of an Inexpensive Carbohydrate Derivative Used as a Chiral Auxiliary in the Synthesis of alpha-Hydroxy Carboxylic Acids. (II) Synthesis of a Potential Carrier for Copper Ions Designed to Be Transported by P-Glycoprotein.
    (2003-11-14) Ballard, Charles Eric; Binghe Wang, Committee Chair; Daniel L. Comins, Committee Member; Jonathan S. Lindsey, Committee Member; Suzanne T. Purrington, Committee Member
    1. Development of an Inexpensive Carbohydrate Derivative Used as a Chiral Auxiliary in the Synthesis of alpha-Hydroxy Carboxylic Acids Protected alpha-hydroxy carboxylic acids were synthesized in moderate yield and high diastereoselectivity by alkylation of glycolate (alpha-hydroxy acetate) enolates using a D-fructose-derived chiral auxiliary. The new chiral center was assigned the R configuration based on comparisons of optical rotations and on one crystal structure analysis. This alkylation methodology is compatible with several hydroxyl protecting groups. The free hydroxy acids were obtained upon removal of the protecting group from the hydroxyl functionality followed by saponification. 2. Synthesis of a Potential Carrier for Copper Ions Designed to Be Transported by P-Glycoprotein Poisoning by heavy metals has traditionally been treated with a handful of nonspecific, highly polar chelating agents. Although the present set of chelators has proven to be valuable as therapeutics, their lack of specificity sometimes results in leaching of essential minerals and their high polarity limits their excretion, such that the metal-chelate complexes are primarily removed by the kidneys. We have developed a potential transporter for copper ions, consisting of a chelator conjugated to a P-glycoprotein transporter substrate. We hypothesize that upon complexation to copper, the complex can be removed by the P-glycoprotein active transporter. Assays that will determine the metal-binding and biological transport properties of the conjugates are planned for later.
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    Using Boronic Acid as the Recognition and Signaling Moiety for Sugar Sensing
    (2004-12-26) Yan, Jun; Bruce Eaton, Committee Member; George H. Wahl, Committee Member; Daniel L. Comins, Committee Member; Binghe Wang, Committee Chair
    The interaction between a boronic acid and a diol is known to be one of the strongest single-pair reversible functional group interactions in an aqueous environment. During the last decade, much effort has been devoted to the development of boronic acid-based sensors for carbohydrates and other diol-containing compounds, and a great deal of progress has been made in this area. However, there are still several fundamental issues that have not been addressed, which hinder the development of such kind of sensors. For example, several factors have long been recognized as important in influencing the binding affinity of boronic acids to diol-containing compound, but there has never been a systematic examination of the relationship among those factors. To address these issues, in Chapter 2 we carefully examined a series of 25 arylboronic acids with various substituents and selected binding affinities with a series of diols at varying pH value. We have found that (1) the pKa of monosubstituted boronic acids can be predicted based on the substituent effect using a Hammet plot; (2) the common belief that boronic acids with lower pKa's have greater binding affinities at neutral pH is not always true; and (3) the optimal pH for binding is not always above the pKa of the boronic acid, instead it is related to the pKa values of both the boronic acid and the diol, although in a manner that cannot be readily predicted. Second, critical to the construction of fluorescent sensors for carbohydrates is the availability of practical fluorescent reporters that respond to the binding event with significant fluorescence intensity changes under physiological conditions. So far a few boronic acid reporters have been described in the literature, but those reporters have undesirable properties such as low water solubility and poor photochemical stability. As described in chapter 2, we have discovered a novel type of fluorescent carbohydrate reporter, 8-quinolineboronic acid (8-QBA). It showed about 40 fold fluorescence increase upon binding of a carbohydrate compound and has very good water solubilty. All these properties make such a system ideal for the construction of fluorescent carbohydrate biosensors for biological applications. With this reporter compound in hand, we designed and syntesized a series of dibornic acids, developed an effective synthetic route for a different kind of 8-QBA-based diboronic acid compound. These results are described in Chapter 4.