The primary goal... ]]> Joomi Ahn http://iris.lib.neu.edu/chemistry_diss/62 http://iris.lib.neu.edu/chemistry_diss/62 Fri, 26 Apr 2013 10:14:32 PDT Protein post-translational modifications (PTMs) play significant roles in affecting the physical, chemical, and biological properties of proteins. PTMs can regulate protein functions by modulating protein activity, turnover, cellular location, and protein-protein interaction. In addition, the efficacy and safety of therapeutic protein drugs can be dramatically affected by PTMs. Structural elucidation of complex PTMs provides invaluable insights for the potential roles of PTMs. However, comprehensive characterization of PTMs presents a significant analytical challenge, often requiring the use of multiple orthogonal methods to ensure high confidence in the resulting analytical data. Liquid chromatography coupled with mass spectrometry (LC-MS) is one of the... ]]> Wenqin Ni http://iris.lib.neu.edu/chemistry_diss/61 http://iris.lib.neu.edu/chemistry_diss/61 Wed, 10 Apr 2013 07:47:44 PDT Protein fluctuation in human serum (such as protein level, variant concentration or post-translational modification) reflects changes in status of an individual. Identification and quantitation of such disease associated proteins in human serum have significant clinical applications, such as diagnosis, prognosis, mechanism elucidation, drug efficacy evaluation. To achieve these goals, various proteomics methods and technologies have been evolving since mid-1990s, taking the challenge of sensitivity, resolution, and throughput.

This dissertation focuses on the study of disease associated proteins in human serum by virtue of various proteomics approaches including affinity, electrophoresis, HPLC, mass spectrometry, etc.. The serum proteome from breast cancer patients... ]]> Zhi Zeng http://iris.lib.neu.edu/chemistry_diss/60 http://iris.lib.neu.edu/chemistry_diss/60 Tue, 12 Mar 2013 10:10:24 PDT Two projects are described in this thesis. The first project was to develop chemical methods for the analysis of protein N-homocysteinylation and the second project was to study the inhibitory mechanism of native brominated furanones on LuxS enzymes. Both projects are related to the metabolism of homocysteine in mammals or bacteria.

Elevated blood levels of homocysteine (Hcy) have been established as an independent risk factor for cardiovascular disease and neurodegenerative disorders, such as Alzheimer's disease. Homocysteine-thiolactone (Hcy TL) is a metabolite of Hcy and reacts with the amino groups in proteins to form N-homocysteinylated (N-Hcy) proteins, which comprise a major... ]]> Tianzhu Zang http://iris.lib.neu.edu/chemistry_diss/59 http://iris.lib.neu.edu/chemistry_diss/59 Mon, 11 Mar 2013 11:45:19 PDT Y family polymerases are a family of DNA polymerases that carry out replication of damaged DNA in a process known as translesion synthesis (TLS) when normal polymerases cannot bypass the damaged base. TLS occurs in two distinct steps: the insertion of a nucleotide opposite the lesion, which can be correct or mutagenic, and the extension step, where 3-6 nucleotides (TLS patch) are added downstream from the lesion so that the normal replicative polymerase can then continue DNA replication. This extension step may be more essential to cell survival than the insertion step. This dissertation presents a comprehensive study to understand... ]]> Jason Michael Walsh http://iris.lib.neu.edu/chemistry_diss/58 http://iris.lib.neu.edu/chemistry_diss/58 Thu, 24 Jan 2013 11:48:47 PST The endocannabinoid system (ECS) encompasses of cannabinoid receptors CB1 and CB2, their endogenous ligands (endocannabinoids), enzymes, proteins and FAAH-like anandamide transporter (FLAT), involved in endocannabinoid formation, transportation and bio-inactivation.^1-3 The ECS is shown to be involved in an ever increasing number of pathological conditions including pain, immune-suppression and appetite disorders and has become an important target for the development of novel medications. Δ⁹-THC, the major psychoactive ingredient of marijuana, produces its physiological response through interaction with two well-characterized cannabinoid receptors (CB1 and CB2).^4,5 Extensive structure-activity relationship (SAR) studies on tricyclic classical cannabinoids have established that the C-3 side chain plays... ]]> Shama Bajaj http://iris.lib.neu.edu/chemistry_diss/57 http://iris.lib.neu.edu/chemistry_diss/57 Wed, 16 Jan 2013 12:03:08 PST Understanding of enzyme function and dynamics has an important role in basic biomedical research. Although many experimental and computational methods have been developed in this field, strong demands still exist for better research tools to solve various problems, such as accurate function annotation of protein structures and efficient interpretation of Electron Spin Resonance (ESR) spectra of spin labeled proteins. This dissertation mainly describes the development of two novel computational methods, Structurally Aligned Local Sites of Activity (SALSA) and Diffusion Operator Approach combined with Rotational Isomer State (RIS) model to investigate problems related to the prediction of enzyme function and to... ]]> Pengcheng Yin http://iris.lib.neu.edu/chemistry_diss/56 http://iris.lib.neu.edu/chemistry_diss/56 Wed, 16 Jan 2013 10:00:54 PST The design of novel selective ligands is important for the structural characterization of G-protein coupled receptors (GPCR). For this reason we have sought to study the interactions of selective cannabinergic ligands with the CB₁ and CB₂ cannabinoid receptors to obtain information on the pharmacophoric requirements for ligand-drug activities.

Our laboratory has developed ligand-assisted protein structure (LAPS) an approach which involves the combined use of covalent ligands, CB1 and CB2 mutants, as well as LC/MS based proteomic methods. We have designed a convergent synthesis for a series of potent and metabolically stable anandamide based covalent ligands. These ligands contain either an... ]]> Kyle M. Whitten http://iris.lib.neu.edu/chemistry_diss/55 http://iris.lib.neu.edu/chemistry_diss/55 Tue, 15 Jan 2013 13:40:52 PST The carbohydrate moiety is important structural motifs in all living organisms and is critically involved and responsible for many biochemical functions and biological activities. Despite the abundance of some naturally occurring carbohydrates, their synthesis is inevitably important in the assembly of complex carbohydrate containing natural compounds, the preparation of unnatural rare sugars, and the delivery of adequate materials for structure–activity relationship (SAR) studies. Our laboratory has successfully developed a de novo approach to synthesize complex carbohydrates from achiral 2-keto-furanyl starting materials. This approach consists of three major steps: (1) syntheses of tert-butyloxycarbonyl pyranone sugar precursors with complete installation of α-/β-D-/L-sugar... ]]> Hua-Yu Wang http://iris.lib.neu.edu/chemistry_diss/54 http://iris.lib.neu.edu/chemistry_diss/54 Tue, 15 Jan 2013 10:15:48 PST Plant-derived and endogenous cannabinoids (endocannabinoids) produce their cellular effects by interacting with cannabinoid receptors (CBs), which are members of the G-protein coupled receptor (GPCR) superfamily. Two subtypes CBRs have been designated as CB₁ and CB₂ which are activated by various CB ligands. These CB ligands have therapeutic potential in numerous medical conditions including obesity, osteoporosis, pain, cancer and inflammation.¹ Cannabinoid ligands bind at orthosteric as well as allosteric binding sites of the receptors. Ligands for both orthosteric and allosteric sites have been synthesized and discussed here.

Cannabinoid agonists Marinol (Dronabinol, Δ⁹-THC) and Cesamet [Nabilone (Eli Lilly)] are marketed to control... ]]> Ritesh B. Tichkule http://iris.lib.neu.edu/chemistry_diss/53 http://iris.lib.neu.edu/chemistry_diss/53 Tue, 15 Jan 2013 07:54:06 PST Molecular modeling can accelerate and guide drug design and contribute to the understanding of the biochemical functions of gene products. This thesis applies molecular modeling to facilitate the drug design for human African trypanosomiasis and develops a new modeling technique for protein biochemical function annotations. A special technique employed in this work is the prediction of the individual amino acids in protein structures that are involved in ligand interactions; these predicted local interaction sites are used for drug discovery and for the prediction of the biochemical function of proteins of unknown function.

Chapter 2 applies molecular modeling to the structure... ]]> Zhouxi (Josie) Wang http://iris.lib.neu.edu/chemistry_diss/52 http://iris.lib.neu.edu/chemistry_diss/52 Fri, 11 Jan 2013 12:58:08 PST Prostaglandin ethanolamides (Prostamides) are an emerging class of endogenous eicosanoids derived from cyclooxygenase (COX) metabolism of the endocannabinoid, anandamide. The chemical structure of the prostamides resembles that of the prostaglandins, with the main distinction attributed to an ethanolamide group in place of the carboxylic acid group. Their biological function has yet to be resolved, however the biosynthetic route for prostamide formation has been well established and their existence in vivo postulated.

While the structures and biosynthetic routes are indeed similar, there is growing evidence that prostamides and their prostaglandin counterparts exhibit diverse biological actions. The substitution of ethanolamide for carboxylic... ]]> Erin Laine Shelnut http://iris.lib.neu.edu/chemistry_diss/51 http://iris.lib.neu.edu/chemistry_diss/51 Fri, 11 Jan 2013 09:55:43 PST The main theme of this dissertation is to develop liquid chromatography electrospray ionization tandem mass spectrometry-based methodologies to investigate isomeric oligonucleotide adducts. The isomeric oligonucleotide adducts formed in reactions between different synthetic oligonucleotide and carcinogenic adducts were investigated. Further, the site selectivity of chemicals belonging to three important families of carcinogens in their reaction with a synthetic oligonucleotide fragment of the tumor suppressor gene, p53, were studied using ion-pair reversed phase nano-liquid chromatography nano-electrospray ionization tandem mass spectrometry. One of the important aspects of the work presented is the use of in-house fabricated polymeric monolithic capillary columns, poly(styrene-divinyl benzene). Another... ]]> Vaneet K. Sharma http://iris.lib.neu.edu/chemistry_diss/50 http://iris.lib.neu.edu/chemistry_diss/50 Tue, 08 Jan 2013 07:10:50 PST Infrared micro-spectroscopy coupled with mathematical algorithms, in which the diagnosis is based on a physical (spectroscopic) measurement and the interpretation is carried out by multivariate statistical algorithms, provides an alternative approach to classical pathology practices. This novel approach is termed Spectral Pathology, where the investigation and diagnosis of disease in cellular specimens is Spectral Cytopathology (SCP), and the study and diagnosis of disease in tissue specimens is Spectral Histopathology (SHP). This methodology provides a robust, objective, and reproducible diagnostic tool where spectroscopic differences reveal intrinsic biochemical changes that can be used as spectral biomarkers to diagnose disease before the manifestation... ]]> Antonella Ida Mazur http://iris.lib.neu.edu/chemistry_diss/49 http://iris.lib.neu.edu/chemistry_diss/49 Thu, 03 Jan 2013 13:00:39 PST The endocannabinoid system includes signaling ligands for the cannabinoid receptors, (CB1, CB2) as well as the enzymes that that are responsible for their biosynthesis and degradation. The two primary endogenous ligands N-arachidonoylethanolamine (AEA) and (2-AG) interact with the CB receptors similar to Δ⁹-tetrahydrocannabinol (THC), a classical cannabinoid isolated from the Cannabis sativa plant. The endocannabinoids AEA and 2-AG are released "on demand" by neurons in the brain as well as in peripheral tissues. Manipulating the concentration of these signaling molecules is an important area of investigation as significant therapeutic benefits are anticipated.

Diacylglycerol lipase (DGL) is a lipid metabolic and... ]]> Meghan Ryan Johnston http://iris.lib.neu.edu/chemistry_diss/48 http://iris.lib.neu.edu/chemistry_diss/48 Fri, 21 Dec 2012 11:11:45 PST DNA replication is responsible for the maintenance of life, ensuring the integrity of the genome from one generation to the next. However, all cells are exposed to a variety of natural and synthetic DNA-damaging agents, which can interfere with DNA replication. Cells have developed, therefore, their own DNA repair systems. It is extremely important to understand the mechanisms of DNA replication and repair, in order to determine how cells survive DNA damage. However, there is still little known about the functional dynamics and conformation ofsome of the accessory proteins in these systems.

In Escherichia coli, UmuD and UmuD′ are DNA-damage... ]]> Jing Fang http://iris.lib.neu.edu/chemistry_diss/47 http://iris.lib.neu.edu/chemistry_diss/47 Wed, 19 Dec 2012 07:59:24 PST Cancer is the second leading cause of death after cardiovascular disease in the United States. Despite extensive research in development of antitumor drugs, most of these therapeutic entities often possess nonspecific toxicity, thus they can only be used to treat tumors in higher doses or more frequently. Because of the cytotoxicity and severe side effects, the drug therapeutic window normally is limited. Beside the toxicity issue, antitumor drug are also not selectively taken up by tumor cells, thus the necessitating concentrations that would eradicate the tumor can often not be used. In addition, tumor cells tend to develop resistance against... ]]> KinhLuan D. Dao