Physical Sciences and Mathematics Commons^™

Atomistic Assessment Of Drug-Phospholipid Interactions Consequent To Cancer Treatment: A Study Of Anthracycline Cardiotoxicity, Yara Elsayed Ahmed

Theses and Dissertations

Despite being one of the most effective chemotherapeutic agents developed to date, Anthracyclines are notorious for their cardiotoxicity. Their clinical use is frequently limited both in dosage and in prescription due to the severe cardiac damage they cause. The mechanism of anthracycline-induced cardiotoxicity is not yet fully understood. However, it is hypothesized that interactions with the myocardial membrane play an important role in imparting cardiotoxicity. In this study, we use molecular dynamics simulations and density functional theory calculations to study the anthracycline drug molecules and the interactions that they have with the myocardial membrane. We construct a myocardial membrane model …

Synthesis Of Bioactive Heterocycles, Shaila Akter Shetu

Theses and Dissertations

The Discovery of a variety of heterocyclic drugs for the treatment of cancer and other diseases (e.g, neglected tropical diseases) is a medical breakthrough and inspiring for the research community as a whole. A wide range of natural, semi-synthetic, and synthetic anticancer drugs are synthesized using various methods. Among them, β -lactams stand out as a novel class of antibiotics that has different types of biological as well as anti-cancer properties. β -lactam has become a premier and active research subject towards the development of revolutionary anti-cancer drugs. In recent years, a large amount of investigations have been done to …

Mechanisms And Impact Of Hypoxia Regulated Inhibins In Cancer, Ben Allen Horst

Theses and Dissertations

Inhibins are heterodimeric ligands within the TGFβ superfamily, comprised of an α-subunit (INHA) and a β-subunit (either INHBA or INHBB) with emergent roles in cancer. Inhibins are biomarkers of disease burden and prognosis in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Previously, we found inhibin promotes angiogenesis in ovarian cancer however no mechanism of regulation for inhibin expression in cancer has been established. Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. …

The Activity Of Qh Ii 66 And It’S Analogs In Medulloblastoma, Melanoma And Non-Small Cell Lung Cancer Cell Lines., Taukir Ahmed

Theses and Dissertations

GABAARs (gamma-aminobutyric acid type A receptors) are transmembrane pentameric ligand-gated chloride ion channels that respond to GABA, the central nervous system's principal inhibitory neurotransmitter (CNS). The benzodiazepines (BZDs) bind between the GABAAR α+γ2-subunits at their extracellular interface. The binding of ligands to distinct subunits of GABAA receptors, notably the α1-6β2/3γ2 ion channels, can have a wide range of effects on brain activities. The sedative, ataxic, amnesic, anticonvulsant, and addictive actions of GABAARs' α1-subtype selective ion channels should be avoided, except for the anticonvulsant and anxiolytic effects, while creating ligands for this BZ allosteric modulatory site. Many studies have linked the …

Development Of A Liquid Biopsy: Using A Synthetic Lectin Array For The Detection Of Cancer, Mary Grace Hollenbeck

Theses and Dissertations

Cancer is the second leading cause of death worldwide with 9.6 million deaths in 2019. It is well known that early detection of cancer often leads to a better prognosis. However, due to drawbacks associated with current cancer screens (i.e. invasiveness, high false positive and negative rates) new or updated early detection methods are needed. Chapter one overviews current breast, colon, and prostate detection methods and the drawbacks associated with them. Additionally, this chapter presents an alternative detection method that utilizes an array of boronic acid functionalized synthetic lectins. We describe the development and progression of this array and show …

Total Synthesis Of Cytotoxic Mansouramycins From Amino Acids, Beatriz Gamez

Theses and Dissertations

Natural products produced by plants, animals, and microorganisms are of significant importance in chemistry for being major sources of molecular scaffolds essential for new drug discovery. Mansouramycins are cytotoxic bioactive compounds containing isoquinoline skeletons with substituents on the quinone and pyridine rings that may be difficult to synthesize. Synthetic processes exist for compounds B and D, however, there exists an absence of simple synthetic approaches to all four alkaloids.

This project aims to provide a general total synthetic pathway to Mansouramycins A—D from amino acids for possible use in cancer treatment via these isoquinolinequinones. Preliminary experimentation suggests there may be …

Chemical Modification And In Silico Validation Of Medicinally Privileged Molecular Scaffolds As Kras And Sars-Cov-2 Protease Inhibitors, Precious M. Okwuchukwu

Theses and Dissertations

Coronavirus disease was declared a global pandemic by WHO in March 2020, cancer is the second leading cause of death by a disease. Several scientists around the world are working relentlessly to discover an effective remedy to eradicate these deadly diseases. A natural polyphenol (magnolol) has been isolated from a tree Magnolia grandiflora (family Magnoliaceae) found on UTRGV campuses. This research is focused on design of a series of chemically modified sulfonyl derivatives based on the isolated magnolol framework and other medicinally privileged molecular scaffolds framework that can effectively bind to the COVID-19 main protease, SARS- CoV-2 3CL protease …

Characterization Of Dna Interstrand Cross-Linking Agents By Liquid Chromatograhy-Mass Spectrometry, Anahit Marina Campbell

Theses and Dissertations

This study is to characterize novel reactive oxygen species (ROS)-activated nitrogen mustard analogues and UV-activated alkylating agents by Liquid Chromatography-Mass Spectrometry (LC-MS). First, we optimized the instrument conditions to successfully ionize a few novel binapthalene analogues and methoxybenzene analogues by MS. The highest signal intensity for compounds 3-10 was observed when atmospheric pressure chemical ionization (APCI) with an optimized corona needle position of 5mm or 10 mm was used, which led to successful analysis of compounds 3-10 by MS. Second, we determined pharmacokinetic properties of a drug compound (FAN-NM-CH3), including animal study, assay development, optimization of MS/MS instrumental parameter and …

Elucidating The Mechanism Of Bone Morphogenetic Protein (Bmp) -Mediated Sox2 Downregulation In Ovarian Cancer, Zainab Motolani Shonibare

Theses and Dissertations

Sex determining region Y-box 2 (Sox2) is a transcription factor essential for maintaining self-renewal and pluripotency of undifferentiated embryonic stem cells. Sox2 is involved in multiple processes of cancer cells, however, regulation of Sox2 expression and the consequences of that regulation in cancer remains elusive. Previously, we demonstrated that BMP9/GDF2 is significantly reduced in expression in ovarian cancer (OVCA) cells, methylated in patient tumors and, promoted anoikis resistance in both breast and OVCA cell lines. In an attempt to identify genes downstream of BMP9 that may provide anoikis resistance, transcriptomics was performed leading to the identification of Sox2, a developmental …

Dually Modified Transmembrane Proteoglycan Tβriii/Betaglycan In Cell Signaling And Cancer, Laura M. Jenkins

Theses and Dissertations

During tumor progression, cancer cells undergo a number of alterations to evade tumor inhibitory mechanisms, proliferate, invade surrounding tissues and metastasize to distant sites. These properties reflect changes in their cell signaling pathways that, in normal cells, control aberrant cell proliferation, motility, and survival. Over the past few decades, hyperactive Wnt/β-catenin signaling has been linked to the formation of multiple cancers, including malignant ovarian cancer, making identification of molecules regulating Wnt/β-catenin signaling crucial to the development of early detection methods and cancer treatment strategies. Proteoglycans, which regulate transmission of cellular signals, are implicated in the pathophysiology of diseases, including cancer, …

Design, Cloning, And Expression Of Rat Preptin And Alanine Analogs, Jahbo M. Love

Theses and Dissertations

Alanine scanning mutagenesis was employed to determine the structural epitopes of preptin; a newly discovered polypeptide found on the proinsulin-like growth factor II. The alanine scanning mutagenesis was accomplished by the use of, cloning, affinity chromatography, gel electrophoresis, gene sequencing, and mass spectra. However, due to inconclusive results, more research is required before the epitopes can be elucidated.

Functional And Mechanistic Insight Into The Role Of Atg9a In Autophagy, Vajira Kaushalya Weerasekara

Theses and Dissertations

The bulk degradative process of macroautophagy requires the dynamic growth of autophagosomes, which carry cellular contents to the lysosome for recycling. Atg9A, a multi-pass transmembrane protein, is an apical regulator of autophagosome growth, yet its regulatory mechanism remains unclear. Our work suggests that hypoxia (low glucose and oxygen) triggers a rearrangement of the small adapter protein 14-3-3ζ interactome. Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3z docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on …

Cdk8 And Cdk19 As Novel Regulators Of Bmp4 Induced Emt In Cancer, Anne Elizabeth Serrao

Theses and Dissertations

Bone morphogenetic protein 2/4 (BMP2/4), members of the transforming growth factor β (Tgf-β) superfamily, play a dichotomous role in the progression of cancers through cell growth suppression and the enhancement of tumorigenesis in a variety of cancers. Cyclin dependent kinase 8 (CDK8), a protein kinase that regulates gene transcription, is involved in a variety of cancers including breast and pancreatic cancers as well as in mediating BMP2 signaling via its canonical Smad1 pathway. Our studies show that BMP4 induced EMT signals primarily though Smad1 and that Yap1, a transcriptional co-activator, is necessary for BMP4 induced EMT. Using a highly specific …

Synthesis, Surface Functionalization, And Biological Testing Of Iron Oxide Nanoparticles For Development As A Cancer Therapeutic, Stanley E. Gilliland Iii

Theses and Dissertations

Iron oxide nanoparticles are highly researched for their use in biomedical applications such as drug delivery, diagnosis, and therapy. The inherent biodegradable and biocompatible nanoparticle properties make them highly advantageous in nanomedicine. The magnetic properties of iron oxide nanoparticles make them promising candidates for magnetic fluid hyperthermia applications. Designing an efficient iron oxide nanoparticle for hyperthermia requires synthetic, surface functionalization, stability, and biological investigations. This research focused on the following three areas: optimizing synthesis conditions for maximum radiofrequency induced magnetic hyperthermia, designing a simple and modifiable surface functionalization method for specific or broad biological stability, and in vitro and in …

Light Controlled Drug Activation And Release, Jonathon Sheldon

Theses and Dissertations

Cancer constitutes a terrible burden on modern society. In the United States there are an estimated 1,658,370 new cancer diagnoses resulting in 589,430 deaths in 2015 alone.^[1] An estimated 41,170 of these cases will be diagnosed right here in Virginia. With new cancer patients comes the expanding demand for new treatments. As we all know, many modern chemotherapeutics cause adverse reactions to patients. This is because the toxic nature of these therapies often affects normal tissue alongside the tumors that are infesting the body. Therefore, researching novel ways to make chemotherapeutics selective for cancer, while leaving healthy tissue unscathed, …

Drug Design, Biological Activity, And Metabolic Consequences Of Cytotoxic Platinum Compounds: Utilizing Fluorescent Tagging To Understand Drug Action And Metabolism, Brad Benedetti

Theses and Dissertations

Platinum drugs are among the most commonly used chemotherapeutics for the treatment of testicular, head and neck, ovarian, small cell lung, and colorectal carcinomas. Although the current set of platinum chemotherapeutics has proven somewhat successful, the overall success of platinum based drugs is limited due to acquired drug resistance and a limited range of tumor types that are treatable with the current regime. The development of novel cytotoxic platinum based compounds, both trans- and polynuclear, provides for the promising treatment of clinical platinum drug resistant tumors. While the cytotoxic activity of platinum drugs provides for a hopeful outlook, the ultimate …

Pyridinium Bis-Retinoids A2-Dopamine And A2-Cadaverine: Implications In Age-Related Macular Degeneration And Cancer, Mckenzie Ruth Pew

Theses and Dissertations

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States of America. The pyridinium bis-retinoid A2-ethanolamine (A2E) has been implicated to play a role in AMD. We have observed novel pyridinium bis-retinoids through melanolipofuscin and human RPE extractions that may also play a role in the pathology of AMD. We have begun the construction of an amino-retinoid library in order to identify these ocular compounds. The compounds from the amino-retinoid library are also used in a targeted and triggered drug delivery system for treating cancer. Folic acid is coupled with the amino-retinoids to specifically target cancer …

Mechanisms Of Accumulation And Biological Consequences Of Polynuclear Platinum Compounds, Peyman Kabolizadeh

Theses and Dissertations

The novel trinuclear complex, BBR3464 has undergone Phase II clinical trials and been shown to have greater cytotoxicity and cellular uptake than clinical anticancer platinum drugs such as cisplatin, oxaliplatin and carboplatin. The clinical efficacy of cisplatin, oxaliplatin and carboplatin is limited due to acquired resistance and dose limiting side effects. The three major pharmacological factors contributing to the intrinsic cytotoxicity of, and cellular resistance to, platinum drugs are (i) cellular uptake and efflux of platinum; (ii) the frequency and nature of Pt-DNA adducts; and (iii) deactivating metabolic reactions with sulfur-containing nucleophiles. Since decreased cellular uptake of platinum drugs is …