Pharmacy and Pharmaceutical Sciences Commons^™

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M. Sammons, Eun Jeong Cho, Pengyu Ren, G. Andrés Cisneros, Jonathan M. Kurie, Kevin N. Dalby

Markey Cancer Center Faculty Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1−18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from …

The Effect Of Heat Treatment And Chemical Treatment On Natural Fibre To The Durability Of Wood Plastic Composites – A Review, Nuratiqah Asyiqin Mohd Nasharudin, Nur Fatihah Sulaiman, Nurul Aziemah Mohammad, Wan Nor Raihan Wan Jaafar, Falah Abu Dr., Siti Norasmah Surip

Journal of Materials Exploration and Findings

The application of WPC is not only limited to indoor applications but has been extended to exterior applications where properties of WPC could compromise during service life. WPC was derived from wood fiber of various sizes to reinforce polymers. Wood fiber has the advantage of a cheaper price, being abundantly available, and ease of processing, however, the critical factor is its hydrophilic nature, where moisture absorption is likely to occur. Thus, treatments for reducing the hydrophilicity of wood fibers are applied. By treatment of wood fiber, the surface impurities were removed, leaving the roughened surface of fibers, thus providing a …

Design, Synthesis, Biological And Computational Studies Of Flavonoid Acetamide Derivatives, Daniel Kasungi Isika

Dissertations

Flavonoid compounds (FC) have extensive biological applications through potent antimicrobial, anti-inflammatory, anticancer, antidiabetic, and antioxidant properties. These applications are nevertheless limited by low bioavailability, poor aqueous solubility, enzymatic degradation, rapid metabolism, and fast body clearance. FC show unique structure-activity relationships (SARs) essential in assessing and mitigating the prevalent challenges impeding their applications. These challenges can be addressed by structural modification of the FC through functionalization of the phenolic rings, modification of the ketone group, and modification of the phenolic hydroxyl groups with bioisosteres.

The objectives of this work are to (i) design and synthesize novel flavonoid acetamide derivatives (FADs) and …

Catecholamine System Function Of The Medial Prefrontal Cortex Following Repetitive Mild Traumatic Brain Injury And The Use Of Benzoyl Chloride To Quantify And Identify Neurotransmitters, Leah Horvat

Theses and Dissertations

Traumatic brain injury (TBI) is a serious global health burden that causes a wide range of neurocognitive symptoms. These cognitive processes are regulated by catecholamine signaling within the prefrontal cortex (PFC) region of the brain. To quantify functional deficits in catecholamine signaling after TBI, norepinephrine (NE) and dopamine (DA) levels within the PFC were quantified from microdialysate samples using high-performance liquid chromatography coupled with electrochemical detection. A method for benzoyl chloride derivatization of neurotransmitters and analysis with liquid chromatography and tandem mass spectrometry instrumentation was also developed to detect and analyze these neurotransmitters. Overall, it was found that catecholamine signaling …

Computer-Aided Drug Design Of Bakuchiol-Inspired Lxrα Modulators Against Acute Lymphoblastic Leukemia, Dillon P. Cao

LSU Master's Theses

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of pediatric malignancies. Although glucocorticoids are commonly used to treat ALL, prolonged use can lead to steroid resistance, rendering the drug regimen ineffective. Therefore, alternative treatment avenues are needed for high- risk pediatric patients that do not respond well to traditional regimens.

Liver X Receptor α (LXRα) is presented as a potential alternative drug target for pediatric patients that exhibit suboptimal response to glucocorticoids. Limitations of the current LXRα modulators such as indiscriminate isoform selectivity between LXRα and LXRβ and consequent adverse effects …

Artemisinin And Its Derivatives Reactions: Characterization Of The Reaction Products Using Lc/Tof Ms, Kogila Vijayan

Theses and Dissertations

Artemisinin (ART) is a sesquiterpene lactone and a popular malaria drug with potential anticancer properties. In this work, LC/TOF MS was used to investigate the reaction of ART with DNA bases and estradiol. ART-deoxyadenosine and ART-deoxycytidine interactions were studied in the presence of Fe (II) ions. ART-deoxyadenosine and ART-deoxycytidine reaction mixtures gave chromatographic signatures that remained unchanged at room temperature but grew after incubation at 37°C. The change in temperature from room temperature to 37°C was the main driver of adduct formation in these reactions. ART was found to react with Fe (II) ions as observed from several new chromatographic …

Computational Study Of Foldamer-Based Water Channels, Shadi Houshyar Azar

Theses and Dissertations

One of the most serious global challenges of this century is water scarcity, stemming primarily from the growing demand for freshwater and the depletion of freshwater resources. Water desalination has the potential to address this problem, but current technologies are expensive and inadequate. Here, we present novel, computationally designed channels with high water permeability and selectivity against ions, inspired by natural water channels, aquaporins. Aquaporin's unique property of transporting water while rejecting protons and other ions has led to numerous studies on incorporating such channels into different membranes for water purification applications. However, use of an aquaporin-incorporated membrane is limited …

Development And Validation Of A Uplc-Ms/Ms Method To Investigate The Plasma Pharmacokinetics Of A KCa2.2/KCa2.3 Positive Allosteric Modulator In Mice, Mohammad Asikur Rahman, Devaraj Venkatapura Chandrashekar, Young-Woo Nam, Basir Syed, David Salehi, Hamidreza Montazeri Aliabadi, Miao Zhang, Reza Mehvar

Pharmacy Faculty Articles and Research

Rationale

There is currently no treatment for spinocerebellar ataxias (SCAs), which are a group of genetic disorders that often cause a lack of coordination, difficulty walking, slurred speech, tremors, and eventually death. Activation of K_Ca2.2/K_Ca2.3 channels reportedly exerts beneficial effects in SCAs. Here, we report the development and validation of an analytical method for quantitating a recently-developed positive allosteric modulator of K_Ca2.2/K_Ca2.3 channels (compound 2q) in mouse plasma.

Methods

Mouse plasma samples (10 μL) containing various concentrations of 2q were subjected to protein precipitation in the presence of a structurally similar internal …

Structure-Guided Mutagenesis Reveals The Catalytic Residue That Controls The Regiospecificity Of C6-Indole Prenyltransferases, Ahmed R. Aoun, Nagaraju Mupparapu, Diem N. Nguyen, Tae Ho Kim, Christopher M. Nguyen, Zhengfeiyue Pan, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

Indole is a significant structural moiety and functionalization of the C−H bond in indole-containing molecules expands their chemical space, and modifies their properties and/or activities. Indole prenyltransferases (IPTs) catalyze the direct regiospecific installation of prenyl moieties on indole-derived compounds. IPTs have shown relaxed substrate flexibility enabling them to be used as tools for indole functionalization. However, the mechanism by which certain IPTs target a specific carbon position is not fully understood. Herein, we use structure-guided site-directed mutagenesis, in vitro enzymatic reactions, kinetics and structural-elucidation of analogs to verify the key catalytic residues that control the regiospecificity of all characterized regiospecific …

Virtual And In Vitro Screening Of Natural Products Identifies Indole And Benzene Derivatives As Inhibitors Of Sars-Cov-2 Main Protease (MPro), Dony Ang, Riley Kendall, Hagop S. Atamian

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The rapid spread of the coronavirus disease 2019 (COVID-19) resulted in serious health, social, and economic consequences. While the development of effective vaccines substantially reduced the severity of symptoms and the associated deaths, we still urgently need effective drugs to further reduce the number of casualties associated with SARS-CoV-2 infections. Machine learning methods both improved and sped up all the different stages of the drug discovery processes by performing complex analyses with enormous datasets. Natural products (NPs) have been used for treating diseases and infections for thousands of years and represent a valuable resource for drug discovery when combined with …

Potential Of Biduri Fiber (Calotropis Gigantea) As Material For Oil Spill Absorbent, Anne Sukmawati, Wulan Septiani

Journal of Materials Exploration and Findings

Biduri fiber (Calotropis gigantea) is a natural hollow fiber with hydrophobic and oleophilic properties potentially used as oil spilled sorbent from seawater. This study aims to determine the absorption capacity and efficiency of the Biduri fiber and membrane to fuel oil. Measurement of oil absorption to seawater was carried out at various fiber weights (0.5-1.5 g), fiber composition (50-95%), contact time (10-90 minutes), temperature (30 and 50°C), and compared with commercial products. The results showed that the fiber weight variation of 0.5-1.5 g has an average absorption efficiency of 96.67%, and the highest absorption was obtained in a weight of …

Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses

Drug metabolism is the biochemical process of modifying drugs to detoxify and remove them through enzymatic transformations. These biotransformation’s occur primarily in the liver and are critical to understanding how pharmaceutical compounds are chemically altered inside the human body. Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19, remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including …

Designing And Synthesizing A Warhead-Fragment Inhibitory Ligand For Ivyp1 Through Fragment-Based Drug Discovery, Samuel Moore

Symposium of Student Scholars

Fragment-based drug discovery (FBDD) is a powerful tool for developing anticancer and antimicrobial agents. Within this, magnetic resonance spectroscopy (NMR) provides a comprehensive qualitative and quantitative approach to screening and validating weak and robust binders with targeted proteins, making NMR among the most attractive strategies in FBDD. Inhibitor of vertebrate lysozyme (Ivyp1) of P. aeruginosa serves as an excellent target because of its active cellular location and implications in clinical prognosis for cystic fibrosis and immunocompromised patients. This study uses current NMR and biophysical techniques to develop a covalent, fragment-linked warhead inhibitor for Ivyp1 through synthetic methods, warhead linking, and …

Synthesis And Characterization Of D5-Barbarin For Use In Barbarin-Related Research, Sucheta Kudrimoti, Jacob Machin, Adedamola S. Arojojoye, Samuel G. Awuah, Rodney Eisenberg, Clara Fenger, George Maylin, Andreas F. Lehner, Thomas Tobin

Maxwell H. Gluck Equine Research Center Faculty Publications

Based on structural similarities and equine administration experiments, Barbarin, 5-phenyl-2-oxazolidinethione from Brassicaceae plants, is a possible source of equine urinary identifications of aminorex, (R,S)-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine, an amphetamine-related US Drug Enforcement Administration (DEA) controlled substance considered illegal in sport horses. We now report the synthesis and certification of d₅-barbarin to facilitate research on the relationship between plant barbarin and such aminorex identifications. D₅-barbarin synthesis commenced with production of d₅-2-oxo-2-phenylacetaldehyde oxime (d₅-oxime) from d₅-acetophenone via butylnitrite in an ethoxide/ethanol solution. This d₅-oxime was then reduced with lithium aluminum …

Managing Risk And Knowledge: Frameworks To Guide Knowledge-Enabled Technology Transfer, Martin Lipa Dr, Anne Greene

Level 3

Technology transfer is not only about the transfer of technology, but also about the transfer of knowledge, as evidenced by definitions of KM within the biopharma industry and beyond. However, knowledge transfer is often not well structured and its effectiveness – in particular for tacit knowledge (i.e., know how) – is an opportunity for improvement which can lead to many benefits. This article profiles recent research into the topic of improving knowledge transfer during technology transfer and presents several recently developed frameworks for improving such. The article furthermore explains how the frameworks can be co-deployed in support of robust knowledge …

Stereocontrolled Access To Δ-Lactone-Fused-Γ-Lactams Bearing Angular Benzylic Quaternary Stereocenters, Timothy K. Beng, Morgan J. Rodriguez, Claire Borg

All Faculty Scholarship for the College of the Sciences

C-fused γ-lactam-lactones are resident in several bioactive molecules, including anticancer agents such as omuralide. In this embodiment, we report mild conditions for the catalytic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids. The use of dichloromethane as the solvent and Ph₃PS as the catalyst led to predominant 6-endo-trig cyclization and furnished the trans-fused-γ-lactam-δ-lactones. The transformation is modular, regioselective, chemoselective, and diastereoselective. The γ-lactam-δ-lactones bear angular quaternary benzylic stereocenters, which is noteworthy since the presence of a quaternary carbon in bioactive small molecules often promotes an element of conformational restriction that imparts potency, selectivity, and metabolic stability. The …

Emerging Technologies: Empowering People To Capture, Share And Transfer Tacit Knowledge, Donncadh J. Nagle, Melanie J. Adams

Level 3

ICH Q10 was published in 2008, and presented a model for an effective Pharmaceutical Quality System (PQS). However, the industry still has some way to go in embracing and implementing its principles in order to achieve greater product realisation, to establish and maintain a state of control, and to facilitate continual improvement.

ICH Q10 introduced us to two key enablers: Knowledge Management (KM) and Quality Risk Management (QRM).^[1] While the pharmaceutical industry has made progress in implementing the principles of QRM since 2008, there has been significantly slower progress in implementing knowledge management practices. However, there may be solutions …

The Design Of A Pcr-Based Assay To Detect And Isolate The Serine Palmitolytransferase Gene From Environmental Bacteria, Lana Taylor

Honors Theses

Sphingolipids are a natural class of lipids that function as structural elements of cell membranes and signaling molecules for important cellular activities such as cell growth, differentiation, apoptosis, recognition, and adhesion. These lipids can be found universally in eukaryotic cells as well as some species of bacteria, such as those found in the human gut microbiome and in the environment in soils. Though sphingolipid production is rare in bacteria, both eukaryotic and prokaryotic sphingolipid biosynthesis begin with the condensation of serine and palmitoyl CoA into 3-ketodihydrosphingosine catalyzed by the enzyme serine palmitoyltransferase (SPT). In recent years, several studies have shown …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

A Proposed Treatment Of Mixed Connective Tissue Disease By Competitive Inhibition Of Autoantibodies, Thomas Russell

Senior Honors Theses

Mixed Connective Tissue Disease is an autoimmune disease characterized by Raynaud’s phenomenon and arthritis among other symptoms. It is primarily caused by antibodies that target the U1-RNP 70K peptide. The treatment proposed in this paper uses competitive inhibition to prevent the binding of the anti-U1-RNP 70K antibodies with the U1-RNP 70K peptide. A method for testing the designed treatment in silico is proposed using AutoDock Vina docking software.

The Development Of Inhibitors For Sars-Cov-2 Orf8, My Thanh Thao Nguyen

CSB and SJU Distinguished Thesis

An unexpected outbreak of SARS-CoV-2 caused a worldwide pandemic in 2020. Many repurposed drugs were tested, but there are currently only three FDA approved antivirals (Merck’s antiviral Molnupiravir, Pfizer’s antiviral Paxlovid, and Remdisivir).1 Most of the antiviral drugs tested SARS-CoV-2 main protease and RNA-dependent RNA polymerase. However, it is important to explore different drug targets of SARS-CoV-2 to prepare for the virus mutations of the future. This research looks at an alternative approach in which SARSCoV- 2 Open Reading Frame 8 (ORF8), which has been shown to be a rapidly evolving hypervariable gene, was chosen to be the protein of …

Sars-Cov-2 Main Protease Inhibitors Repurposed For Hiv-1 Protease Binding, Jacob Minkkinen

CSB and SJU Distinguished Thesis

Severe acute respiratory syndrome (SARS-CoV-2) led to the COVID-19 global pandemic, with over 460 million cases of infection and over 6 million deaths since the start of the pandemic. SARS-CoV-2 is a retrovirus that utilizes a main protease (Mpro). Mpro is a catalytic cys/his protease. Several treatments were proposed to stop the pandemic including repurposing drugs to inhibit the Mpro. Another retrovirus that uses a protease is human immunodeficiency virus (HIV-1) which has been a global epidemic for 40 years and is a devastating disease that attacks the immune system. HIV-1 has infected 79.5 million people and has killed an …

A Quantitative Analysis Of The Efficacy Of Various Essential Oils Against The Sars Cov-2 Virus, Elizabeth Wagstaff, Chandrelyn Kraczek, Jack Brandon Lopez

Annual Research Symposium

A poster presentation and abstract for the Roseman Symposium. The project focuses on testing 3 essential oil blends and two disinfectants containing an essential oil blend against SARS CoV-2 in response to the COVID-19 pandemic. The project procedure involves plaque assays, disinfection, and neutralization techniques.

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance Of Tumor Cells And Modulate Signaling Pathways, Victoria Abzianidze, Natalia Moiseeva, Diana Suponina, Sofya Zakharenkova, Nadezhda Rogovskaya, Lidia Laletina, Alvin A. Holder, Denis Krivorotov, Alexander Bogachenkov, Alexander Garabadzhiu, Anton Ukolov, Vyacheslav Kosorukov

Chemistry & Biochemistry Faculty Publications

n the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds …

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Investigating The Physical Stability Of Amorphous Pharmaceutical Formulations, Travis W. Jarrells

Theses and Dissertations--Pharmacy

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in …

Development Of Accurate And Efficient Computational Methodologies For Predicting Protein-Ligand And Protein-Protein Binding Free Energies, Alexander Hamilton Williams

Theses and Dissertations--Pharmacy

Computational modeling is an invaluable tool in the drug discovery process either for small ligand or protein therapeutics. The widespread availability of protein X-Ray Crystal and Cryo-Electron Microscopy (Cryo-EM) structures has allowed for more accurate molecular dynamics (MD) simulations that are not reliant on methods such as homology modeling, which may produce structures that require significant computational time to demonstrate their stability. In this thesis we describe several novel methodologies for the computationally efficient modeling of protein/ligand and protein/protein complexes that may be employed within both large-scale virtual screenings and lead compound optimization. These methodologies may also be utilized in …

Peripherally Restricted Opioid Conjugates And Its Use As Pharmacological Probes And Potential Therapeutics, Md Tariqul Haque Tuhin

University of the Pacific Theses and Dissertations

Opioid-induced constipation (OIC) is one of the major adverse effects of opioid analgesics used by millions of patients each year. While progress has been made, there remains a significant unmet medical need in the treatment of OIC. Major gaps remain in our understanding of the role of the gastrointestinal tract and central nervous system (CNS) in precipitating OIC. For the last four decades, numerous investigations to study the sites of action of opioid analgesics have utilized peripherally acting mu-opioid receptor antagonists (PAMORAs), which have been incorrectly believed to have limited penetration across the blood-brain barrier (BBB). Several preclinical and clinical …

The Vagabond Flourine Atom Revisited: Dissociative Photoionization Of Tri- And Pentafluoropropene, Jessica K. De La Cruz

University of the Pacific Theses and Dissertations

Photoelectron Photoion Coincidence (PEPICO) Spectroscopy studies on two unsaturated hydrofluorocarbons (HFCs), also known as hydrofluoroolefines (HFOs), are presented here. Previously, the Sztáray group has studied the dissociation of trans-1,3,3,3-tetrafluoroprop-1-ene (ElixClean), which is a fourth-generation refrigerant and propellant and has lower global warming potential than its precursors. My study is an extension of the ElixClean study as it aims to explore how the different number of fluorine atoms impact the dissociation reactions of these molecules. Both 3,3,3-trifluoropropene (TFP) and cis-1,2,3,3,3- pentafluoropropene (PFP) are also utilized as propellants and refrigerants.Measurements were carried out with remote access to the CRF-PEPICO (combustion reactions followed …

Gc/Ms And Lc/Ms Approaches To Chemical Communication In Plants And Marine Cyanobacteria, Carolyn Keim

University of the Pacific Theses and Dissertations

Natural products are small organic compounds synthesized by living organisms including plants, animals, and microbes. These fall into one of two categories, primary metabolites are required for survival, but secondary metabolites usually play a more accessory role. Extracts from organisms have proven to be useful to humans throughout history. Prior to evidence-based western medicine practices, natural products were the only source of medicine and remain as a treatment source for underdeveloped nations. Today, natural products have either been approved by or have served as the template for many FDA approved drugs. Based on a survey of all FDA approved drugs …