Medicine and Health Sciences Commons^™

Discovery Of Novel Tubulin Inhibitors And Selective Survivin Inhibitors For Advanced Melanoma And Total Synthesis Of Bioactive 20s-Hydroxyvitamin D3, Qinghui Wang

Theses and Dissertations (ETD)

According to the statistics from American Cancer Society, the 5-year survival rate for patients with advanced melanoma is as low as 5%. Treatment of advanced melanoma, therefore, represents an unmet medical need. In this dissertation, I will show the effort to develop new generations of bioavailable tubulin inhibitors targeting the colchicine binding site and selective small-molecule survivin inhibitors for treating advanced melanoma. Extensive structure-activity relationship (SAR) studies of lead molecules ABI-231 and UC-112 have been performed.

Chapter 1 will introduce the current situation of advanced or metastatic melanoma, its clinical drug treatments, as well as problems in current drug treatments. …

Translational Pharmacokinetic-Pharmacodynamic Modeling And Simulation In The Development Of Spectinamides, A Novel Class Of Anti-Tuberculosis Agents, Chetan Rathi

Theses and Dissertations (ETD)

New chemotherapeutic agents are urgently needed to control the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of tuberculosis, which still remains an important public health challenge globally. Recently, spectinamides have emerged as a novel class of anti-tuberculosis agents that overcomethe native drug efflux. Spectinamides bind to the 30S bacterial ribosomal subunit which interferes with ribosomal translocation, and ultimately results in inhibition of protein synthesis. They have potent in vitro activity against drug resistant Mycobacterium tuberculosis (Mtb), and also demonstrated sustained efficacy in (Mtb)-infected mouse models. Pharmacokinetic (PK)/ pharmacodynamic (PD) analyses play a critical role in identifying …

The Development Of Methods To Account For Physiologic Dynamic Changes And Their Effects On The Pharmacokinetics Of Therapeutic Monoclonal Antibodies And Other Therapeutics, Josiah Thomas Ryman

Theses and Dissertations (ETD)

Physiologic changes in the body can drastically affect the clearance of a medication, and therefore increase the variability in exposure to the medication. Physiologic changes that can have a profound effect on the exposure of a medication can stem from changes CYP enzymes, transport proteins, binding protein expression, organ function, immune reactivity, and health status to name a few; with the focus of this dissertation on the dynamic changes in the ontogeny of MRP2 (an apical liver transport protein) and the dynamic changes caused by an immune response to a therapeutic monoclonal antibody (mAb). Several approaches can be used to …

Synthesis Of 20s-Hydroxyvitamin D3 Analogs And Their 1Α-Hydroxyl Derivatives As Potent Anti-Inflammatory Agents, Zongtao Lin

Theses and Dissertations (ETD)

Rheumatoid arthritis (RA) is one of the autoimmune diseases, and is affecting 2.5 million Americans in total. Among the treatment options of RA, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the only steroidal drug used clinically for anti-inflammatory and immune diseases. However, long-term use of 1,25(OH)2D3 (625 µg/day) in human would result in hypercalcemia (toxicity), and 1,25(OH)2D3 has substantial hypercalcemic effects (toxicity) in mice at a dose as low as only 2 µg/kg. Fortunately, during the investigation of novel metabolic pathway of vitamin D3 by cytochrome P450 enzymes, we found 20S-hydroxyvitamin D3 [20S(OH)D3] as a good lead compound. 20S(OH)D3 suppressed disease symptoms at …

Age-Associated Expression Patterns Of Oatp 1b1 And Oatp 1b3 And Their Effect On The Disposition Of Fexofenadine, Margaret Mary Thomson

Theses and Dissertations (ETD)

As part of the drug disposition process (absorption, distribution, metabolism, excretion), an often overlooked aspect is transport. In order for drugs to be metabolized and excreted from the body they go through the liver or other drug removal organs. For drugs that are polar or are large they must rely upon transport mechanisms to transport them across the biomembranes of the drug removal organs. OATP1B1 and OATP1B3 are transporters on the sinusoidal membrane of the liver which work in concert with the drug metabolizing enzymes as part of the drug removal process. It is known that the development of each …

Design, Synthesis, And Evaluation Of Novel Positron Emission Tomography Radiotracers, Christopher Philip Surdock

Theses and Dissertations (ETD)

Neuroblastoma (NB) is the most common extracranial tumor in patients under 1 year of age and it constitutes about 8-10% of all childhood cancer. It originates from neural crest cells that normally differentiate to form the sympathetic ganglia, adrenal medulla and other paraspinal sites where sympathetic nervous system tissue is present. Even with an extensive treatment regimen that typically includes surgery, chemotherapy, total body irradiation and autologous stem cell transplantation, the 5-year event-free survival is <50% for high risk patients, and there are numerous long-term side effects associated with treatment. This body of work investigated two projects for improving patient outcomes through the development of positron emission tomography (PET) radiotracers that could be used for therapy planning. The goal of the first project was to design, synthesize, and evaluate PET radiotracers that could measure the enzymatic activation of Irinotecan (CPT-11), a potent chemotherapeutic used in the treatment of colon cancer and several pediatric solid tumors. CPT-11 itself is a prodrug which is converted in vivo to SN-38, via metabolism by carboxylesterase (CE) enzymes. St. Jude Children’s Research Hospital researchers have designed a two-pronged protocol of tumor-targeted CPT-11 chemotherapy combining the complementary approaches of a) specific modulation of human CE in normal tissues to improve drug delivery, and b) tumor-targeted activation of prodrug using neural progenitor cells (NPC) transfected with a mutant human CE cDNA. The tumor-selective trafficking of NPC allows over-expression of CE within the tumor. This prodrug/activating enzyme therapeutic approach has shown extremely encouraging preclinical results in the treatment of NB (90% 1-year survival in mice). However, successful translation of this novel therapeutic approach into general clinical practice requires a better understanding of progenitor cell trafficking, duration and intensity of enzymatic activity and the ultimate biological fate of the therapeutic construct. Toward this end, PET radiotracers were developed based on extensive structure-activity relationship (SAR) studies of CE binding. The goal of the second project was to design, synthesize, and evaluate PET radiotracers that could identify the presence of the tropomyosin receptor kinase B (TrkB). TrkB is not normally found in sympathetic nervous tissue, which is the tissue NB develops from, and thus is a potential target for imaging and therapy. The presence of TrkB and its neurotrophin, brain derived neurotrophic factor (BDNF), have been reported to protect neuroblastoma tumor cells from chemotherapy-induced apoptosis via a phosphatidylinositol 3’-kinase pathway. Radiotracers were synthesized and evaluated for their ability to identify TrkB both in vitro and in vivo. PET radiosynthetic procedures were optimized to synthesize novel radiotracers for imaging targets that could help clinicians monitor therapy or identify markers that would aid in therapy planning for NB patients. The method development could be applied to future compounds that show improved chemical characteristics for synthesis and selectivity.

Biodegradable Polymeric Biomaterials In Different Forms For Long-Acting Contraception And Drug Delivery To The Eye And Brain, Dileep Reddy Janagam

Theses and Dissertations (ETD)

Efficacy of many of the new and existing therapeutics is often hampered by the lack of an effective and compliant method of delivery. Typically, drugs have poor water solubility, short half-lives, and low permeability across the biological membranes. The result is low bioavailability of the drugs at the target site and can cause toxicity and side effects at high doses. Often the conventional dosage forms fail to overcome these limitations. In the recent decades, biodegradable polymeric drug delivery systems have emerged as promising candidates to solve the challenges of poor solubility, low permeability and sustained release owing to the advantages …

Cannabinoid Receptor 2 (Cb2) Ligands Downregulate Pro-Inflammatory Markers In Stimulated Primary Human Periodontal Ligament Fibroblasts (Hpdlfs), Ammaar Hasan Abidi

Theses and Dissertations (ETD)

There are approximately 743 million individuals suffering from chronic periodontitis (PD) making it the sixth most prevalent condition worldwide. The affected adult population in the U.S. are nearly 64.7 million and the healthcare costs exceeds $14 billion. Recently, host response to pathogenic infection has been seen critical to the progression of PD and exhibit increase in various inflammatory markers. Marijuana is well known for its recreational usage and is a risk factor for periodontal disease, which is seen as a concern in society for its negative health consequences. However, many medical conditions can benefit from the pharmacological effects of cannabinoids. …

Discovery Of Natural Product-Based Antimycobacterial Agents Effective Against Non-Replicating Bacilli, Shajila Siricilla

Theses and Dissertations (ETD)

New antimycobacterial molecules that kill non-replicating Mycobacterium tuberculosis (Mtb) were identified by screening libraries of synthetic natural products. De novo screening of a 400-membered library of aurachin RE analogs resulted in discovery of UT-317 ((R)-20). UT-317 is a selective vitamin K2 biosynthesis (MenA) inhibitor that killed replicating and non-replicating Mtb at 2.31 μg/mL (MIC) and 0.85 μg/mL, respectively. A 50-membered library of capuramycin analogs was evaluated in their enzymatic inhibitory activities against translocase I (MraY/MurX) and prenyl-phosphate-GlcNAc-1-phosphate transferase (WecA). UT-01320 (45) is identified as a selective WecA inhibitor that kills both replicating and non-replicating Mtb at 1.50 μg/mL (MIC) and …

Biophysical And Biochemical Screening Approaches For Antimicrobial Drug Discovery Targeting S. Aureus Clpp, Aman Preet Singh

Theses and Dissertations (ETD)

The discovery of antibacterial drugs has been among most significant achievements of mankind in saving millions of lives across the planet from infectious diseases. With rise in resistance to almost all existing chemotypes, the design of next generation novel antibiotics has become much more challenging and difficult. The early 21st century witnessed the advancement of multiple novel chemotypes during golden age of antibiotics however the pace of antibiotic drug discovery has slowed down tremendously, contributing to life threatening antimicrobial discovery void since 1980’s. Therefore the need to develop novel antibiotics with unique mechanism of action to leverage against multi drug …