Medicinal Chemistry and Pharmaceutics Commons^™

Investigation Of Bacteria From The Trachymyrmex Septentrionalis Fungus Garden For Potential Antibacterial Drug Leads, Brendan Stewart

University Scholar Projects

Bacterial and fungal strains are growing resistance to antibiotics and antifungal agents at an alarming rate. According to the Centers for Disease Control and Prevention, over two million people in the United States in 2016 were diagnosed with an infection resistant to antibiotics. As such, there has been increased interest in natural products as sources of novel compounds that are essential to the development of new drugs and treatment methods. Within the environment, there are various host-microbe symbioses, one of which is the Trachymyrmex septentrionalis leaf-cutter ant community. The microbes in symbioses like the T. septentrionalis community are hypothesized to …

Investigation Of Bacteria From The Trachymyrmex Septentrionalis Fungus Garden For Potential Antibacterial Drug Leads, Brendan Stewart

Honors Scholar Theses

Bacterial and fungal strains are growing resistance to antibiotics and antifungal agents at an alarming rate. According to the Centers for Disease Control and Prevention, over two million people in the United States in 2016 were diagnosed with an infection resistant to antibiotics. As such, there has been increased interest in natural products as sources of novel compounds that are essential to the development of new drugs and treatment methods. Within the environment, there are various host-microbe symbioses, one of which is the Trachymyrmex septentrionalis leaf-cutter ant community. The microbes in symbioses like the T. septentrionalis community are hypothesized to …

Evaluating The Aryl Hydrocarbon Receptor As A Target For Pharmacologic Activity Of Repurposed Drugs, Teofilo Borunda Duque

Pharmaceutical Sciences ETDs

The discovery of new pharmacologic targets is important for the advancement of pharmacotherapy and identification of new indications for current drugs. The aryl hydrocarbon receptor (AHR) is a physiologic sensor of both chemical environmental pollutants and ligands of natural origin. Given the broad spectrum of ligands that activate the AHR and its relationship with toxicology, the AHR is not thought to be a traditional target for pharmacotherapy. However, multiple studies have shown potential for the AHR as a novel pharmacologic target Therefore, identifying less toxic agents that modulate the AHR may elucidate mechanisms for pharmacological targeting of the AHR. The …

Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow

Dissertations and Theses (Open Access)

Skp2 (S-phase kinase-associated protein 2), one component of the SCF E3 ubiquitin ligase complex, directly interacts with Skp1 and indirectly associates with Cullin1 and Rbx1 to bridge the E2 conjugating enzyme with its protein substrate to execute its E3 ligase activity. Skp2 is an Fbox protein (due to it containing an Fbox domain) and it is the rate-limiting component of the SCF complex. Skp2 targets several cell-cycle regulatory proteins for ubiquitination and degradation; most notable and significant for cancer are the cyclin-dependent kinase inhibitor, p27. Skp2 is an oncogene and studies have shown that over-expression of Skp2 leads to increased …

Signal Detection Of Adverse Drug Reaction Using The Adverse Event Reporting System: Literature Review And Novel Methods, Minh H. Pham

USF Tampa Graduate Theses and Dissertations

One of the objectives of the U.S. Food and Drug Administration is to protect the public health through post-marketing drug safety surveillance, also known as Pharmacovigilance. An inexpensive and efficient method to inspect post-marketing drug safety is to use data mining algorithms on electronic health records to discover associations between drugs and adverse events.

The purpose of this study is two-fold. First, we review the methods and algorithms proposed in the literature for identifying association drug interactions to an adverse event and discuss their advantages and drawbacks. Second, we attempt to adapt some novel methods that have been used in …

Developing Novel Therapeutics For Bacterial Lung Infections, Brandon J. Baer, Ruud Veldhuizen, Cory Yamashita

Western Research Forum

Background: Bacterial lung infections are leading causes of death worldwide. Unfortunately, increasing resistance to antibiotics and the inflammation often accompanying these infections are leading to poor outcomes despite antibiotic intervention. Complicating treatment further, the tree-like branching structure of the lung makes drug delivery to distal sites of infection difficult. Our research aims to address these challenges by developing new therapeutics and new tools to improve and assess drug delivery, bacterial killing and inflammation. Our therapy combines host defense peptides, which have been shown to kill antibiotic-resistant bacteria and down regulate inflammation, with a pulmonary vehicle, exogenous surfactant, that can improve …

Drug Delivery Strategies For The Treatment Of Advanced Lung Cancer And Various Lung Metastases, Elizabeth Bielski

Wayne State University Dissertations

Lung cancer remains the leading cause of cancer-related deaths in the United States. Secondary lung tumors metastasized from other cancer sites also remains highly prevalent, in which most metastatic tumors cannot be cured with existing therapies. Chemoresistance (multi drug resistance – MDR) that develops intrinsically or acquired is one of the key factors leading to fatality in these patients. MDR develops form a variety of resistance mechanisms that can occur consecutively or concurrently, therefore, making most current treatments unsuccessful. Current therapies have known to slow tumor growth, but rarely provide a cure. Immunotherapy has seen some promise, including the use …

Medicinal Properties Of Cyperus Species (Sedge Family, Cyperaceae), Lata Maishaya Udari

Masters Theses

The grasses that yield therapeutically important products are among the least studied in the Cyperaceae family. Herb-based medicine from ancient times have played a vital role in ailments of various disease and nowadays it has been a particular area of interest in medicine. Phytochemicals are inherent compounds derived from plants that are biologically active, non-nutritive chemicals that act as a defensive or prophylactic medicine in humans. Their extracts have proven to show inhibition properties against different microbes. Despite the prevalence of Cyperus species and their traditional use in medicine, the chemical components responsible for their attributes remain largely unknown. This …

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 …

Buspirone Hydrochloride, Jaslene Garcia

Natural Sciences Student Research Presentations

This poster for the Natural Sciences Poster Session at Parkland College provides information on Buspirone Hydrochloride, trade name BuSpar, used to manage anxiety disorders. Chemical information, dosage, and the body's reaction to the medication are included.

The Development Of Novel Non-Peptide Proteasome Inhibitors For The Treatment Of Solid Tumors, Zachary C. Miller

Theses and Dissertations--Pharmacy

The proteasome is a large protein complex which is responsible for the majority of protein degradation in eukaryotes. Following FDA approval of the first proteasome inhibitor bortezomib for the treatment of multiple myeloma (MM) in 2003, there has been an increasing awareness of the significant therapeutic potential of proteasome inhibitors in the treatment of cancer. As of 2017, three proteasome inhibitors are approved for the treatment of MM but in clinical trials with patients bearing solid tumors these existing proteasome inhibitors have demonstrated poor results. Notably, all three FDA-approved proteasome inhibitors rely on the combination a peptide backbone and reactive …

Carbazole Based Multifunctional Dopamine Agonists And Related Molecules As Potential Symptomatic And Disease Modifying Therapeutic Agents For Parkinson’S Disease, Asma S.Mohamed Elmabruk

Wayne State University Dissertations

Parkinson’s disease (PD) is a progressive neurodegenerative disease that develops from gradual depletion of dopamine (DA) and dopaminergic neurons in the substantia nigra pars compacta (SNc) with the accumulation of intraneuronal proteinaceous matter named as Lewy bodies. The four cardinal symptoms associated with PD are tremor, rigidity, bradykinesia, and postural instability. Although the exact mechanism and etiology of PD are not fully understood, several factors have been implicated in the pathogenesis and progression of PD including protein aggregation, oxidative stress, mitochondrial dysfunction, environmental, and genetic factors.

The current therapy of Parkinson’s disease is categorized into four classes: levodopa, DA agonists, …

Discovery Of Piperlongumine Derivatives As Anti-Leukemic And Anti-Prostate Cancer Agents, Yi Liao

Wayne State University Dissertations

Piperlongumine (PL) is an electrophilic anti-cancer natural product. Through non-covalent or covalent interactions with cellular targets, PL inactivates multiple oncogenic pathways and suppresses key components of cellular anti-oxidant/anti-electrophile defense systems. These actions result in pleiotropic anticancer effects and are expected to be effective to heterogeneous acute myeloid leukemia (AML) and prostate cancer (PCa). We applied two approaches to enhance the anticancer potency of PL: 1) To design PL-histone deacetylase inhibitor hybrid drugs (PL-HDACis; e.g., 1-58), and 2) To dimerize PL pharmacophore to generate a dimeric PL (DiPL) warhead that is suitable for further conjugation (e.g., 5-17). Both 1-58 and 5-17 …

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 …

Study Of The Mechanism Of Action For Ru(Ii) Polypyridyl Complexes As Potential Anticancer Agents, Yang Sun

Theses and Dissertations--Chemistry

Application of chemotherapeutic agents in current cancer treatment has been limited by adverse effects as poor selectivity results in systemic toxicity; most chemotherapy approaches also experience inherited or acquired drug resistance which lead to reduced treatment outcome. Research efforts have focused on the discovery of novel chemotherapies that overcome the limitations mentioned above. Ru(II) polypyridyl complexes with anti-cancer properties have been extensively studied as traditional cytotoxic agents and photodynamic therapy agents due to their photophysical and photochemical characteristics.

Most research has focused on the design of Ru(II) polypyridyl complexes that have affinities to nucleic acids as inspired by the classic …

Tumor Multicomponent Targeting Polymer-Lipid Hybrid Nanoparticles To Overcome Drug Resistance In Renal Cell Carcinoma, Hashem Obaid Alsaab

Wayne State University Dissertations

Renal Cell Carcinoma (RCC) contributes to more than 90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the United States. Although surgery remains an option for operable tumors, high metastatic index and resistance to radiation and chemotherapies prompted recent development of therapeutics that target the RCC angiogenesis and cell proliferation pathways. Tyrosine kinase inhibitors or TKIs (Cabozantinib, Axitinib, Sorafenib, and Sunitinib) and mammalian target of rapamycin (mTOR) inhibitors (Temsirolimus and Everolimus) have increased the therapeutic options for treating RCC. Although the impact towards decreasing disease progression is encouraging, …

Design, Synthesis And Biological Evaluation Of Pyrido[2,3-D]Pyrimidines As Inhibitors Of N5-Cair Synthetase, Qian Lin

Wayne State University Dissertations

The spread of drug-resistant bacterial infections has increased the need for novel antimicrobial agents. One potential but unexplored target is the de novo purine biosynthetic pathway. PurK, found only in bacteria, yeast, and fungi, catalyzes the sixth step in purine biosynthesis and has no human homolog. Herein we disclose the discovery of the first PurK inhibitor with submicromolar potency.

PurK is a member of the ATP-grasp superfamily of enzymes and recently, nanomolar inhibitors of biotin carboxylase, a related enzyme, were published. We hypothesized that those inhibitors, which target the ATP-binding site, could also inhibit PurK. To explore this hypothesis, four …

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

Targeting Ribosome Assembly Factors Selectively Protects P53 Positive Cells From Chemotherapeutic Agents, Russell T. Sapio, Anastasiya Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, N. Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Many chemotherapeutic agents act in a nondiscriminatory fashion, targeting both cancerous and noncancerous cells in Sphase and Mphase. One approach to reduce the toxic side effects in normal tissue is to exploit the differences in p53 functionality between cancerous and noncancerous cells. For example, activating p53 signaling by nongenotoxic means can transiently arrest noncancerous p53 positive cells in G1 phase and protect them from the cytotoxic effects of chemotherapeutic drugs. However, since most cancerous cells have faulty p53 signaling, they will proceed to cycle, and continue to be affected by the drug. In this study we asked if this G1‐phase …

In Silico Study Of Newly Synthesized Opioid Analgesics Bound To Three Opioid Receptors, Abdullah Allaoa, Mai Zahran

Publications and Research

Opioids are the most widely used drugs for the treatment of moderate to severe, chronic pain. They achieve antinociception by activation of mu (MOR-1), kappa (KOR-1), and delta (DOR-1) opioid receptors. Natural products found in kratom plant, Mitragyna speciosa, represent diverse chemical groups with opioid activity, providing opportunities to better understand opioid pharmacology. Pharmacology studies show that Mitragynine pseudoindoxyl is a mu agonist/delta antagonist opioid with a signaling bias for G-protein-mediated signaling pathways in vitro and which produced potent antinociception in vivo. Respiratory depression assays along with other behavioral testing also showed that some of the major problems …