Alumni Dissertations and Theses

 
 

Alumni Dissertations and Theses

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  • GROUND- AND EXCITED-STATE CHEMISTRY OF [BIS(2,2'-BIPYRIDINE)(2-(2-PYRIDYL)PYRAZINE) RUTHENIUM(II)]: PROTONATION AND COORDINATION

    Author:
    Elena Ferloni
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Harry Gafney
    Abstract:

    Ruthenium(II) diimines have been extensively studied for their notable photo physical properties. Of particular interest are compounds with ligands with peripheral base sites, where the metal-to-ligand charge transfer shifts electron density onto the ligand yielding an emissive state of increased in basicity. One well known example of such complexes, (bis(2,2'-bipyridine) (2-3-bis(2-pyridyl) pyrazine) ruthenium(II), [Ru(bpy)2dpp]2+, has been studied extensively, yet questions remained regarding the sequence of protonation steps at the two peripheral dpp nitrogens in the ground and excited states and the magnitude of the photo-induced change in acid-base properties at each site. In order to reach a deeper understanding of the kinetic and thermodynamic steps involved in its protonation and coordination, a similar complex was synthesized and studied, (bis(2,2'-bipyridine) (2-(2-pyridyl) pyrazine) ruthenium(II), [(bpy)2Ru(pypz)]2+. The alternative ligand is identical in almost every respect to dpp except for the absence of the free pyridyl ring and the fact that it has only one possible protonation site instead of two. The pypz ligand, thus, represents an ideal candidate to elucidate how the pyrazinyl nitrogen on the coordinated dpp would behave if the additional pyridyl ring on dpp was not present. The differences and similarities in the properties of [(bpy)2Ru(pypz)]2+ and [Ru(bpy)2dpp]2+ in the same environment are highlighted here, describing the peculiar behavior of the acid-base sites of each complex upon excitation and their role in protonation reactions and coordination reactions to d10 metals, namely zinc.

  • IMINOPHOSPHORANES AS USEFUL PRECURSORS TO POTENTIAL TRANSITION METAL-BASED CANCER CHEMOTHERAPEUTICS

    Author:
    Malgorzata Frik
    Year of Dissertation:
    2015
    Program:
    Chemistry
    Advisor:
    Maria Contel
    Abstract:

    During the past two decades, gold(III), platinum(II), palladium(II) and ruthenium(II) compounds have been investigated as potential anticancer drugs. Our group at Brooklyn College reported on the cytotoxic properties of neutral and cationic gold(III), palladium(II) and platinum(II) complexes with iminophosphoranes (IM) or iminophosphine ligands of the general formula R3P=NR’. These IM ligands have been very useful to synthesize and stabilize compounds of d8 transition metals which displayed higher toxicity against leukemia, prostate cancer and ovarian cancer cells when compared to normal T-lymphocytes. They also seemed to have a mode of action different from that of cisplatin. This thesis describes the synthesis of coordination and organometallic, gold(III), platinum(II), palladium(II) and ruthenium(II) complexes with different iminophosphorane ligands, the study of their stability in solution by different techniques and of their interaction with biological targets (mostly DNA and HSA). I have also included data on the biological activity of these compounds (in vitro and for selected complexes in vivo) to understand their potential as cancer chemotherapeutics. Most of these compounds have displayed excellent anticancer properties by a mode of action different from that currently accepted for cisplatin and, in some cases, have displayed a lower toxicity, better activity or better permeability in vivo. These results are described in three different chapters as summarized below. In Chapter III, I describe the synthesis and characterization of a series of coordination gold(III), palladium(II), and platinum(II) complexes with a luminescent IM ligand derived from 8-aminoquinoline [Ph3P=N-C9H6N]. The coordination palladium(II) and platinum(II) compounds can evolve further, under appropriate conditions, to give stable cyclometalated endo species [M{κ3-C,N,N-C6H4(PPh2=N-8-C9H6N}Cl] (M = Pd, Pt) by C-H activation of the phenyl group of the PPh3 fragment. The compounds have been evaluated for their antiproliferative properties in a human ovarian cancer cell line (A2780S), in human lung cancer cells (A-549) and in a non-tumorigenic human embryonic kidney cell line (HEK-293T). Most compounds have been more toxic to the ovarian cancer cell line than to the non-tumorigenic cell line. The new complexes interact with human serum albumin (HSA) faster than cisplatin. Studies of the interactions of the compounds with DNA indicate that, in some cases, they exert anticancer effects in vitro based on different mechanisms of action with respect to cisplatin. The stability of cyclometallated compounds is markedly higher than that of coordination complexes. In Chapter IV, I describe the synthesis, characterization and stability studies of new organometallic gold(III) and platinum(II) complexes containing cyclometalated IM ligands. Most compounds are more cytotoxic to a number of human cancer cell lines than cisplatin. A cationic Pt(II) derivative ([Pt{κ2-C,N-C6H4(PPh2=N(C6H5)(COD)](PF6)) displays IC50 values in the sub-micromolar range. Its cell death mechanism is mainly through caspase-dependent apoptosis but it triggers caspase-independent cell death when apoptosis is blocked. Permeability studies by two different assays: in vitro caco-2 monolayers and a rat perfusion model have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100% which potentially makes it a good candidate for oral administration. Lastly in Chapter V, I describe the synthesis, characterization and stability studies of a series of organometallic ruthenium(II) complexes containing iminophosphorane ligands. These cationic compounds with chloride as counterion are highly soluble in water (70-100 mg/mL). Most compounds (especially the highly water-soluble compound- ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, non-dependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of ([(η6-p-cymene)Ru{(Ph3P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl) on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo.

  • Synthesis and Evaluation of Sensitizer Drug Photorelease Chemistry: Micro-Optic Method Applied to Singlet Oxygen Generation and Drug Delivery

    Author:
    Goutam Ghosh
    Year of Dissertation:
    2014
    Program:
    Chemistry
    Advisor:
    Alexander Greer
    Abstract:

    This thesis summarizes a new micro-optic method for singlet oxygen generation and sensitizer drug delivery, which include i) synthesis and evaluation of a first generation device for drug delivery from native and fluorinated silica probe tips, ii) synthesis of PEG conjugated sensitizers to study phototoxicity in ovarian cancer cells, and iii) synthesis and evaluation of tris-PEGylated chlorin conjugated fluorinated silica for its future integration into the device to use as a 2nd generation device. A first generation micro-optic device was developed that works by sparging O2 gas and light generating cytotoxic singlet oxygen that cleaves the covalently attached drug (sensitizer) from the probe tip at the distal end of the fiber. The aim is to develop a 1st and 2nd generation device for site specific delivery of photosensitizer and singlet oxygen to overcome the challenges involved in systemic administration of the sensitizer. Synthesis and evaluation of drug (pheophorbide-a) delivery applying micro-optic method from native and fluorinated silica probe tip was achieved. The amount of sensitizer photocleavage depends on the loading level of sensitizer onto the probe tips. We also found that photorelease efficiency depends on the nature of the solvents where sensitizer is photocleaved. For example, no photorelease was observed in an aqueous solvent where sensitizer remained adsorbed to the native silica probe-tip. But, 90% photocleavage was obtained in octanol. A significant amount of photosensitizer (formate ester of pyropheophorbide-a) diffused into the liposome when photocleavage study was carried out in liposome. Substantial increase of photorelease was observed in organic solvent when pyropheophorbide-a (PPa) sensitizer was attached to the partially fluorinated porous Vycor glass. We also explored sensitizer photorelease from the fluorinated silica surface at various temperatures and we found that autocatalytic photorelease happened at room temperature and above. No photorelease was observed at low temperature. Chlorin e6 and its one, two and three short chain methoxy triethylene glycol (PEG) conjugated derivatives were synthesized. A comparative study of photocytotoxicity and cellular uptake between each showed that 173,152,131- chlorin e6 methoxy triethylene glycol triester has the highest photocytotoxic activity and uptake by ovarian OVCAR-5 cancer cells. Therefore, we decided to load three short chain PEG conjugated chlorin e6 onto the silica surface through spacer alkene for delivery via a fiber-optic probe tip. In order to load chlorin e6-triPEG ester conjugate, in chapter 4, we explored different synthetic strategies. We have been successful in synthesizing spacer alkene succinate linker conjugated chlorin e6-tri PEG ester, which was attached to the fiber-optic probe tip. Reactions were carried out in mild conditions to avoid detachment of the PEG ester from the carboxylic acid sites of chlorin. Photocleavage of the triPEG modified fluorinated probe tip system was studied in n-butanol.

  • BIOPHYSICAL STUDIES OF MOLECULAR RECOGNITION IN PERIPHERAL AND INTEGRAL MEMBRANE PROTEINS

    Author:
    Xudong Guan
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Ruth Stark
    Abstract:

    The molecular interactions of peripheral and integral membrane proteins with ligands and model biological membranes play important roles in the regulation of human nutrition, cell signaling, and other physiological processes. In the current study, we have used solution- and solid-state nuclear magnetic resonance (NMR) and computational modeling methods to study the interactions of fatty acid-binding proteins (FABPs) with ligands and membrane mimetics, and to examine the conformation of a transmembrane peptide fragment of the Ste2p G protein-coupled receptor (GPCR) in lipids. Computational docking with NMR-derived restraints has been used to identify critical ligand-protein electrostatic interactions in both an intermediate singly-liganded state and the double-liganded liver fatty acid-binding protein (LFABP). The model structure for a R122L/S124A LFABP mutant reveals that two charged residues are required to ensure that the first oleate ligand adopts an orientation and conformation favoring binding of the second ligand within the protein cavity. A detailed model for the ligand binding process is proposed based on the analysis of these docked structures and solution-state NMR structures determined previously. A new isotropically tumbling bilayered micelle (bicelle) system composed of dimyristoylphosophatidylcholine (DMPC) and 1,2-di-O-hexyl-sn-glycero-3-phosphocholine (DIOHPC) has been assessed as a membrane-mimetic medium and used to probe molecular interactions with two FABPs. Rat intestinal fatty acid-binding protein (IFABP) and LFABP were titrated with the bicelles, with site-specific changes monitored by chemical shift perturbations. Contrasting transfer mechanisms for fatty acids between FABPs and membranes were differentiated based on their respective chemical shift perturbations, and site-specific information was deduced about the IFABP-membrane interaction. Additionally, both solution- and solid-state NMR have been utilized to investigate a double transmembrane peptide (TM1TM2) from the Ste2p GPCR in phospholipid environments. A solution-state NMR interaction study of the 15N alanine-labeled peptide with DMPC-sodium docecylsulfate detergent mixtures demonstrated successful reconstitution into a helical conformation, whereas solid-state NMR experiments on TM1TM2 in DMPC multilayers permitted assignment of some signals by residue type.

  • Synthesis of Biologically important C-glycoinositols

    Author:
    Sunej Hans
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    David Mootoo
    Abstract:

    Glycosylinositol subunits comprise important glycoproteins on eurkayotic cell membranes and oligosaccharide components of the cell wall of mycobacteria. Glycosylinositols are also believed to function as secondary messengers in cellular processes, such as the mediation of insulin action. Analogues of glycoinositols in which the ring or glycosidic oxygen of the acetal residue is replaced with a methylene group (C- and carba- glycoside respectively), have attracted interest as mechanistic probes because of their greater hydrolytic stability and different conformational behavior compared with the native O-glycosides. Chapter 1 of this thesis presents an overview of selected biologically important glycoinositols, and of previous synthetic approaches to C- and carba- glycosides. Chapters 2, 3 and 4 describes the synthesis of the C-glycosides of 6-O- (a-mannosyl)-myo-inositol and 4-O- (2-amino-2-deoxy-b-D-galactopyranosyl)-3-O-methyl-D-chiro-inositol (also called INS-2), and the carba-glycoside of INS-2. The synthetic strategy for these complex C- and carba- glycosides centers on formulation of the "sugar" or "glycone" component from a highly oxygenated cyclic enol ether in which the enolic oxygen is endo- or exo- cyclic, respectively. A key innovative element in these syntheses is an oxocarbenium ion cyclization strategy wherein these enol ethers are produced with complete stereocontrol from highly substituted thioacetal-enol ether precursors. An appealing aspect of this plan is that the cyclization precursors may be accessed in a convergent fashion starting from the esterification of "glycone" and "aglycone" components, thereby allowing for the preparation of a variety of C- or carba- inositols with different sugar and inositol residues.

  • CHEMICAL, BIOLOGICAL AND ANALYTICAL STUDIES ON NATURAL PRODUCTS FROM CENTRAL NERVOUS SYSTEM- (CNS) ACTIVE PLANTS

    Author:
    Fang He
    Year of Dissertation:
    2013
    Program:
    Chemistry
    Advisor:
    Wayne Harding
    Abstract:

    Abstract CHEMICAL, BIOLOGICAL AND ANALYTICAL STUDIES ON NATURAL PRODUCTS FROM CENTRAL NERVOUS SYSTEM- (CNS) ACTIVE PLANTS by Fang He Adviser: Professor Wayne W. Harding There are several CNS activities, including analgesic, antidepressant, sedative, euphoric, stimulant, anxiolytic, psychedelic and oneirogenic activity. Investigation of CNS-active plants has the promise to identify new compounds that may be therapeutically useful or that may be useful as probes for CNS receptors. This thesis deals with three plants that have been reported to possess CNS activity: Leonotis leonurus, Silene capensis, and Ipomoea indica. Leonotis leonurus when smoked or consumed as a tea is reported to cause mild marijuana-like sedative effects. Our investigation has uncovered three new labdane diterpenes from an aqueous extract of a commercial source of the plant. The labdane diterpenes tested did not show any CNS receptor affinity at the sites we tested. These compounds are not likely (by themselves) to be responsible for the activity. Silene capensis known as African Dream Root has oneirogenic activity. Phytochemical isolation of our plant material resulted in the isolation of ten known compounds. Six of these ten compounds are withanolides or withanolide glycosides. No phytochemical investigations of Ipomoea indica have been reported to date. Eight known compounds were isolated during our investigation.

  • Fabrication and Assembly of Patchy Particles with Uniform Patches

    Author:
    Zhenping He
    Year of Dissertation:
    2014
    Program:
    Chemistry
    Advisor:
    Ilona Kretzschmar
    Abstract:

    Patchy colloidal particles have been widely studied as the self-assembly building blocks to illustrate their potential for forming complex structures. The parameters affecting the final assembly structures include (i) patch size, shape, and number per particle, (ii) their relative positions, and (iii) the surface properties of the patch material. Recent computational studies have highlighted the impact of patch shape on assembly structure; however, there are only a limited number of methods that can provide control over patch shape and size. In this thesis, a template is introduced to the Glancing Angle Vapor Deposition method (GLAD) to create surface anisotropy on colloidal particles with uniform and controlled patch size and shape. Further, a mathematical model is derived that instructs the patchy particle fabrication process and also assists in the quantitative description of patch area. The template-assisted GLAD method is used to fabricate patchy particles, i.e., colloidal particles with a predefined patch on their surface. The patch size is controlled by varying the incident angle and rotation angle when particle size and template dimension are fixed. Due to the shadowing effect of the template and adjacent particles, a large variety of patch shapes can be achieved, including but not limited to symmetric semi-spherical caps and asymmetric crescent moon and triangular-shaped patches. A second vapor deposition enables the addition of another patch, which partly overlaps with the first patch. The mathematical model provides instruction on selecting adequate parameters to achieve a specific patch shape. In addition, it can also be used to calculate the patch size. In the model, the patch shape is defined in a three-dimensional space thereby enabling the description of various patch shapes obtained from the different fabrication parameters. Last but not least, the model also predicts patch position and calculates the size of the overlapping region of two patches. Overall, the template-assisted GLAD method is illustrated to be a powerful tool for the control of patch size, shape and uniformity, while providing the opportunity for scalability and reduced occurrence of defects. Such patchy particles with a specific patch shape and/or multiple patches made of different materials have great potential to provide more intricate assembly structures and potential applications.

  • Highly-selective Chemiresistive Sensing and Analysis of Vapors Using Functionalized Nanotubes

    Author:
    Deon Hines
    Year of Dissertation:
    2015
    Program:
    Chemistry
    Advisor:
    Daniel Akins
    Abstract:

    Specifically, the project involves the development of a diversified array of nanostructured gas-sensors comprised of selectively, novel surface-functionalized carbon nanotubes (for analyte selectivity by virtue of functionality). Harnessing carbon nanotubes with various electron withdrawing and donating groups help in determining their affinity toward certain prognostic gaseous markers thus increasing specificity of such created sensors. We have devised synthetic routes that have led to the facile production of covalently polyfunctionalized nanotubes in high yield. Seven carbon nanotube analogues were systematically considered and then chemically synthesized, from pristine single-walled nanotubes (SWNT's), for use as the main component of sensory units that was used for this study. The basic chemical structure of these functionalized nanotubes; namely: poly(p-phenol)-co-SWNT [1], poly(p-nitrobenzene)-co-SWNT [2], poly(p-fluorobenzene)-co-SWNT [3], poly(p-aniline)-co-SWNT [4], polybromide-SWNT [5] , poly(p-thiophenol-co-SWNT [6] and poly(p-benzonitrile-co-SWNT [7]. The ability to manufacture total organic sensors was demonstrated using carbon nanotube based architectures. These derivatized-nanotube-based materials are designed to serve as chemoreceptors that can facilitate the development of highly selective and sensitive chemical and biological sensor arrays through an "electronic nose" approach which mimics the mammalian olfactory system. Functionalized SWNTs (f-SWNTs) were dispersed in dimethyl formamide (DMF) and mCresol and spun-applied to the interdigitated regions of micro-lithographically fabricated, pre-cleaned interdigitated microsensor electrodes (IME 1025-M-Pt and Au). Measured changes in the electrical conductivities of an array of gas sensors upon exposure to selected vapors and inert explosive materials were monitored. These changes are transduced into electrical signals, which are preprocessed and conditioned before identification by a pattern recognition system. Preliminary chemisensory was conducted on four signature vapor components of RDX explosive. Sensor data from these individual detection methods was assessed by their own individual merits, after which they were amalgamate and reclassified to present each vapor as a unique data point on a 2-dimensional map and with a minimum loss of information. Extensive characterizations on the properties of these materials were carried out using various spectroscopic and electrical techniques to assess the usefulness of functionalized single-walled carbon nanotubes. It was found that the conductivity of two functionalized materials (poly(p-aniline)-co-SWNT [4] and polybromide-SWNT [5] ) were more conductive than the pristine SWNT. The development of consistent and successful functionalization techniques that allows for the construction of CNTs-based species of great usefulness, reversibility and selectivity for the use as sensing element, can be a challenge. We have demonstrated a proof-of-concept by exploring and using the functionalized carbon nanotubes for use as gas sensors, through the utilization of a stochastic fingerprinting methodology. However, further studies into electronic and electrochemical detection methods will provide more unique systems for R&D on the applicability of these materials to future technology.

  • DEVELOPMENT AND APPLICATIONS OF MASS SPECTROMETRIC METHODS FOR PHOSPHORYLATION ANALYSIS

    Author:
    Hsin-Pin Ho
    Year of Dissertation:
    2014
    Program:
    Chemistry
    Advisor:
    Emmanuel Chang
    Abstract:

    Protein phosphorylation modification regulates numerous cellular functions by a reversible and selective control of kinases and phosphatases. To understand the entire dynamic network of phosphorylation requires sensitive and reliable quantification of phosphorylation, measurements that can be achieved by mass spectrometry. In this research, we established efficient MALDI-mass spectrometric methods as strategies for single- or multi-site phosphorylation quantification without the use of isotopes, chromatography and calibration curves. The methods were assessed by analyzing peptide standards with different single-multiple phosphorylation sites, showing a wide dynamic range, good accuracy and reproducibility. This is the first label-free MALDI method without using a calibration methodology proposed for quantification of in vitro phosphorylation in a kinase assay. Moreover, advanced mass spectrometry empowers identification of a highly conserved Cdk2 phosphorylation site of HIV-1 reverse transcriptase (RT) at Thr 261 across thousands of HIV-1 strains. We demonstrated phosphorylation on HIV-1 RT peptides and protein in in vitro assays, and confirmed phosphorylation in vivo with antibodies and mutation studies. Blocking this phosphorylation by p21, a naturally occurring Cdk inhibitor, defines a potential Cdk2-mediated cell-intrinsic mechanism for restricting HIV-replication in a clinically significant way.

  • Design of Ultra-large-pore Ordered Mesoporous Silicas and Grafting of Organic Groups on Their Surfaces

    Author:
    Liang Huang
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Michal Kruk
    Abstract:

    Developing novel methods to synthesize ordered mesoporous silicas with ultra-large pores and exploring robust approaches to functionalize their surfaces are two attractive topics in material science. Focused on these two aspects, this dissertation includes the selection of swelling agents for the synthesis of ordered mesoporous silicas templated by commercially available surfactants, and the development of diverse surface modification strategies to graft functional molecules on the surface of ordered mesoporous silicas. In chapter 2, the synthesis of FDU-12 silicas with face-centered cubic structure of ultra-large mesopores was described. Xylene was identified as a superior swelling agent, which worked perfectly with Pluronic F127 (EO106PO70EO106). The unit-cell parameter of FDU-12 silicas was expanded up to 56 nm, and the pore diameter reached 36 nm without the loss of structural ordering. The acid treatment effectively suppressed the structural shrinkage. Ethylbezene was proven to be another powerful swelling agent comparable with xylene. Highly ordered closed-pore FDU-12 silicas were prepared via a simple thermally-induced pore closure process at temperatures as low as 400-450 °C. In chapter 3, grafting of organic groups on surfaces of ordered mesoporous silicas was discussed. Polymers were grafted either by growing from the initiation sites on the surface of the solid support ("grafting from") or attached to the surface by forming covalent bond between the chain ends and the functional groups on the surface ("grafting to"). Polymer/FDU-12 silica composites were obtained by surface-initiated atom transfer radical polymerization (SI-ATRP) or surface-initiated atom transfer radical polymerization with activators regenerated by electron transfer (SI-ARGET ATRP). Good control of the polymerizations was observed in organic and protic media. The Huisgen azide-alkyne cycloaddition "click" reaction and thiol-ene "click" reaction were employed for grafting organic groups to the surfaces of SBA-15 silicas. The alkyne-azide "click" reaction was highly effective for grafting various azide molecules including low-molecular weight polymers to the inner surface of mesopores. The thiol-ene "click" was found less effective but still suitable for the "grafting to" method in nanopores.