Medicinal-Pharmaceutical Chemistry Commons^™

Progress Towards Next Generation Modulators Of Ctbp's Oncogenic Effects, Jacqueline L. West

Theses and Dissertations

Human C-terminal binding proteins (CtBP1 and CtBP2) are transcriptional coregulators of multiple genes in the human genome, including tumor suppressor genes (e.g., Bik, PTEN, BRCA1, and E-cadherin) as well as oncogenes (e.g. MDR1 and Tiam1). Both homologues of CtBP are overexpressed in many types of cancer, including breast cancer (92%), ovarian cancer (83%), colorectal cancer (64%), hepatocellular carcinoma (60%), gastric cancer, prostate cancer, and pancreatic adenocarcinoma. Further, expression levels of CtBP correlate with worse prognostic outcomes and more aggressive tumor features because it promotes proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal activity.

Our laboratory has identified a lead inhibitor …

Bisphosohoglycertae Mutase: A Potential Target For Sickle Cell Disease, Anfal S. Aljahdali

Theses and Dissertations

Bisphosphoglycerate mutase (BPGM) is a part of the erythrocyte glycolysis system. Specifically, it is a central enzyme in the Rapoport-Leubering pathway, a side glycolytic pathway involved in the regulation of the concentration of the natural allosteric effector of hemoglobin (Hb), 2,3-bisphosphoglycerate (2,3-BPG). BPGM catalyses the synthesis and hydrolysis of 2,3-BPG through its synthase and phosphatase activities. The synthase activity is the main role of BPGM, while the phosphatase activity is low and is activated by the physiological effector, 2-phosphoglycolate (2-PG) with the latter mechanism poorly understood.

BPGM activity and 2,3-BPG levels in red blood cells (RBCs) have a significant role …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Heparan Sulfate. A Ligand For Coordination Compounds., Eric Ginsburg

Theses and Dissertations

Heparan sulfate (HS), a type of glycosaminoglycan (GAG), has been identified as a ligand for interactions with polynuclear platinum complexes (PPCs). HS is involved in numerous biological processes, and often considered to be extracellular DNA. PPCs interact with HS through the formation of a “sulfate clamp”, where multiple anionic sulfate groups cluster around the cationic PPC. The masking of HS results in the inhibition of enzymatic activity, protein-HS interactions, and other biological processes. PPCs use HS proteoglycans as an method of cellular internalization. By targeting sulfated-GAGs, PPCs can offer precision medicine not currently observed with the FDA approved platinum therapies. …

Towards A Greener Route To Blockbuster Statin Drugs: Harnessing The Power Of Biocatalysis And Integrating Cross-Coupling Catalysis In The Synthesis Of Rosuvastatin, Chanaka M. Amarasekarage

Theses and Dissertations

As global and political awareness about green and sustainable practices sharpens in the face of dramatic climate change and environmentally detrimental practices, one attractive approach is to harness the catalytic potential of enzymes. Thus influenced, our efforts focused on the development of an innovative chemoenzymatic route to widely prescribed Blockbuster statin drugs, specifically rosuvastatin. In this work, we engineered novel deoxyribose phosphate aldolase (DERA) variants via rationally designed site-directed mutagenesis to accept non-natural, less polar substrate, acrolein, along with acetaldehyde. Several of new mutants displayed elevated tolerance towards aldehydes and showed effective incorporation of acrolein into the unprecedented enzymatically-derived chiral …

An Enzymology And Inhibition Study Of A Camp-Dependent Protein Kinase Linked To Acth-Independent Cushing's Syndrome, Nicole Luzi

Theses and Dissertations

Cyclic-AMP dependent protein kinase (PKA) is a key intracellular signal transduction kinase that is modulated by G_s- and G_i-coupled GPCRs. Under normal physiological conditions, PKA exists as an inactive holoenzyme made up of two catalytic subunits and two regulatory subunits. Upon cAMP binding to the regulatory subunits, the catalytic subunits (PKACa) are released to perform various downstream phosphorylation events. However, aberrant PKA activation can cause various diseases including Cushing’s Syndrome, which is an endocrine disorder caused by the overproduction of cortisol by the hypothalamus-pituitary-adrenal hormone system. This disorder can be caused by pituitary adenomas that release …

5-Ht2b Receptor-Mediated Cardiac Valvulopathy, Pallavi Nistala

Theses and Dissertations

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens …

The Forensic Characterization Of Bacterial And Fungal Organisms In Traditional Chinese Medicine, Julia Grzymkowski, Christopher J. Ehrhardt, Justin L. Poklis, Michelle R. Peace

Undergraduate Research Posters

There has been an increase in use of Traditional Chinese Medicine (TCM) in the United States because they are less expensive and believed to be more effective with less adverse effects in comparison to traditional pharmaceutics. Therefore, sales have increased in the US, despite articles and case studies demonstrating the dangers, such as injury and death, related to TCM, stemming from improper labelling, toxic contaminants, and, in some cases, the presence of pathogenic bacteria. The aim of this study was to perform a survival experiment to demonstrate the importance of proper herbal brewing technique and to conduct a molecular and …

Improving Binding Affinity Through Cyclization, Kaylee M. Newcomb, Nicolas Abrigo

Undergraduate Research Posters

Cancer chemotherapy results in systematic damage as the drugs used are also toxic to benign tissue. Sensitizing a cancer cell to therapy by interfering with the DNA repair mechanisms would decrease overall toxicity, as the necessary dosage of chemotherapy drugs would be lowered. The Hartman lab developed a peptide (8.6) that binds with a KD of 1 μM to the C-terminal domain of breast cancer associated protein (BRCA1), blocking homologous recombination. The crystal structure of the peptide shows the tyrosine and threonine residues are close together, suggesting that by cyclizing these positions, the peptide may already be constrained into its …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Development Of Non-Traditional Platinum Anticancer Agents: Trans-Platinum Planar Amine Compounds And Polynuclear Platinum Compounds, Daniel E. Lee

Theses and Dissertations

Development of Non-Traditional Platinum Anticancer Agents: trans-Platinum Planar Amine Compounds and Polynuclear Platinum Compounds

By Daniel E. Lee, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015

Major Director: Nicholas P Farrell, Ph.D., Professor, Department of Chemistry

Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied …

Physicochemical And Structural Analysis Of Polymers As Putative Drugs, Meghan L. Thompson

Theses and Dissertations

Sulfated low molecular weight lignins (LMWLs) have shown good activity as anticoagulants by allosterically inhibiting thrombin, as well as promising agents for treating emphysema through inhibition of elastolysis, oxidation, and inflammation. Sulfated LMWLs are chemo-enzymatically synthesized from starting monomers caffeic, ferulic, and sinapic acid into sulfated dehydropolymers known as CDS, FDS, and SDS. To further the LMWLs’ development as drugs, their structural composition and physicochemical characteristics were defined in this work. The molecular weight distribution profile of the sulfated LMWLs from size exclusion chromatography performed on a high pressure liquid chromatography system (SEC-HPLC) changed from bimodal when no surfactant is …