Medicinal and Pharmaceutical Chemistry Commons^™

Modulation Of Antibacterial Activity And Cytotoxicity In Amphipathic Cyclic Peptide [R4w4] Using Histidine Substitution, Ryan Stueber

Pharmaceutical Sciences (MS) Theses

Antibiotics have been the gold standard frontline defense against bacterial infections for decades. At the same time, these infecting bacteria have continued to evolve to resist developed antibiotics in an almost endless cycle. As such, we aim to take an alternative approach utilizing antimicrobial peptides (AMPs) as a means to end this cycle. [R4W4] is among known AMPs that demonstrated antimicrobial activity against methicillin-resistant staphylococcus aureus (MRSA) with a minimum inhibitory concentration (MIC) of 2.67 μg/mL. This peptide had notably effective antimicrobial activity, especially relative to linear (R4W4). However, it displayed a concerning level of cytotoxicity; eliciting a human embryonic …

Mcl-1 Inhibition: Managing Malignancy In Multiple Myeloma., Omar Al-Odat, Max Von Suskil, Robert Chitren, Weam Elbezanti, Sandeep Srivastava, Tulin Budak-Alpddogan, Subash C. Jonnalagadda, Bharat Aggarwal, Manoj Pandey

College of Science & Mathematics Departmental Research

Multiple myeloma (MM) is a plasma cells neoplasm. The overexpression of Bcl-2 family proteins, particularly myeloid cell leukemia 1 (Mcl-1), plays a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis of MM. Thus, inhibition of the Mcl-1 protein considered as a therapeutic strategy to kill the myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. This review presents the critical role of Mcl-1 in the progression of MM, the most prominent BH3 mimetic and semi-BH3 mimetic that selectively inhibit Mcl-1, and …

Development Of Vaccines And Antivirals Against Zika Virus, Aryamav Pattnaik

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

The re-emergence of Zika virus (ZIKV), an arbovirus, poses a major global human health concern because of its ability to cause congenital abnormalities and neurological diseases. While many candidate vaccines and antiviral drugs are in the developmental pipeline, none have been approved for use against ZIKV infection. This dissertation describes the characterization of one vaccine and two antiviral drug candidates against ZIKV infection. A bacterial ferritin-based nanoparticle vaccine, termed zDIII-F, is designed to display multiple copies of ZIKV E protein domain III on its surface. These stable nanoparticles are shown to induce robust antibody-mediated protection against lethal ZIKV infection in …

Computational Study Of Drug Interactions Of Receptors, Specifically Glycoprotein D Of Human Herpes Virus 1 And Dopamine D4 Receptor, Griffin Fountain

Theses and Dissertations

This thesis introduces computer-aided drug design methods in Chapter 1 and discuss their applications on two receptors in Chapters 2 and 3: Glycoprotein D (gD) of Herpes Simplex Virus 1 (HSV-1) and Dopamine Receptor D4 (DRD4). The Herpes Simplex Virus is a human pathogen that develops unpleasant cold sores around the body, most commonly around the mouth, neck or genitals area. Currently there is no cure or vaccine that can eliminate this virus. Glycoprotein D (gD) is a viral ligand for host cell receptors such as nectin -1. This interaction mediates the entry of HSV-1. In chapter 2, we used …

Behavioral Analysis Of Conditions And Treatments Affecting Movement And Nociception, Indu Mithra Madhuranthakam

Theses and Dissertations

This thesis work includes three projects. First part deals with the investigation of novel D2 receptor ligands in Prepulse inhibition. The goal of this study is to establish a relationship between dopamine receptor antagonists and agonists and prepulse inhibition which can then serve as a working model for an in-vivo efficacy of novel dopamine D2 drugs. The second part of the thesis work deals with Niemann pick disease type C. Niemann pick disease type C is a progressive genetic disorder that is characterized by the lysosomal accumulation of lipids which causes neurodegeneration, dementia, ataxia, and death. NPC1_nmf164 mutant mice …

Differential Effect Of Proinflammatory Cytokines On Corneal And Conjunctival Epithelial Cell Mucins And Glycocalyx, Kiumars Shamloo, Priya Mistry, Ashley Barbarino, Christopher Ross, Vishal Jhanji

Pharmacy Faculty Articles and Research

Purpose: Ocular surface mucins and glycocalyx are critical for providing ocular hydration as well lubrication and repelling pathogens or allergens. Elevated levels of tear proinflammatory cytokines in dry eye may have detrimental effect on mucins and glycocalyx. The present study tested the effect of proinflammatory cytokines IL-6, TNF-α, and IFN-γ on membrane-tethered mucins expression, glycocalyx, and viability of ocular surface epithelial cells.

Methods: Stratified cultures of human corneal and conjunctival epithelial cells were exposed to different concentrations of IL-6, TNF-α, and IFN-γ for 24 hours. The mucins gene and protein expressions were quantified by real-time polymerase chain reaction …

Engineering And Characterization Of Human Β-Defensin-3 And Its Analogues And Microcin J25 Peptides Against Mannheimia Haemolytica And Bovine Neutrophils, Harpreet Dhingra, Kamaljit Kaur, Baljit Singh

Pharmacy Faculty Articles and Research

Mannheimia haemolytica-induced bovine respiratory disease causes loss of millions of dollars to Canadian cattle industry. Current antimicrobials are proving to be ineffective and leave residues in meat. Antimicrobial peptides (AMPs) may be effective against M. haemolytica while minimizing the risk of drug residues. Cationic AMPs can kill bacteria through interactions with the anionic bacterial membrane. Human β-Defensin 3 (HBD3) and microcin J25 (MccJ25) are AMPs with potent activity against many Gram-negative bacteria. We tested the microbicidal activity of wild-type HBD3, three HBD3 peptide analogues (28 amino acid, 20AA, and 10AA) derived from the sequence of natural HBD3, and MccJ25 …

Efforts Toward Novel Methods For The Synthesis Of Stereochemically-Dense Pharmacologically Relevant Scaffolds, Lauren Nicole Tumbelty

Theses and Dissertations

Nitrogen is the most common pure element, present in nearly all relevant chemical compounds. It is an essential component of the building blocks of life such as proteins, nucleic acids, amino acids and adenosine tri-phosphate. There is a naturally occurring exchange between living organisms and the atmosphere which begins with the process of fixation. Although nitrogen is naturally abundant, the strength of the triple bond in atmospheric nitrogen prevents its applicability in organic synthesis. Therefore, the development of methods to place synthetic nitrogen into heteroatomic compounds plays an important role in the development of pharmacologically relevant scaffolds. Contained within this …

Design, Synthesis And Antineoplastic Evaluation Of A Variety Of Small Molecule Scaffolds, Bader Huwaimel

Theses & Dissertations

Several appealing strategies emerged for selective anticancer therapy. Mitochondrial respiratory complex II (CII) is a potential target for many human diseases, including cancer. We have designed, synthesized, and characterized a library of potent CII inhibitors atpenin A5 and diazoxide analogs with enhanced ‘drug-likeness’ and evaluated their antineoplastic activity. Several of these derivatives showed greater activity and selectivity to inhibit the CII. Design aspects of lead derivatives (16c) include optimum ligand lipophilicity efficiency of >5, and half-life of >3 hours. This derivative displayed potent and selective inhibition of cell proliferation in both multiple human prostate cancer cell lines and …

Modification And Antichlamydial Activity Evaluation On Dysregulators Of Cylindrical Proteases, Jiachen Feng

Theses & Dissertations

Chlamydia trachomatis infection is the most commonly reported sexually transmitted disease in the United States and the world. This pathogen can cause long-term health problems including blindness, pelvic inflammatory disease (PID) and ectopic pregnancy, which can be life-threatening if left untreated. To this day, there is no chlamydia-specific drug on the market. The standard treatment uses broad-spectrum antibiotics, which may affect regular functions of the commensal microbiota and leads to the development of bacterial resistance. Recently, a series of compounds based on Activators of Self-Compartmentalizing Proteases (ACP) was reported to show antichlamydial activity. Based on that scaffold, we prepared 21 …

Design, Synthesis And Evaluation Of Novel Inhibitors Of Type 5 And 10 17Β-Hydroxysteroid Dehydrogenases, Ahmed Morsy

Theses & Dissertations

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are essential enzymes in steroid metabolism. More and more evidence points to the pivotal contributions of these enzymes in various other metabolic pathways. Therefore, the latest research results give new insights into the complex metabolic interconnectivity of the 17β-HSDs with human diseases. This dissertation focuses on the metabolic activities of type 5 and 10 17β-HSDs. More specifically, regarding 17β-HSD5 contributions to the progression of prostate cancer (PCa) and 17β-HSD10 aggravation of amyloid-beta (Aβ)-induced toxicity in Alzheimer's disease (AD).

The second leading cause of cancer-related death in males is PCa, with the highest incidence rate of all cancers …

Lipoxin A 4 (Lxa 4 ) Promotes Reduction And Antibiotic Efficacy Against Pseudomonas Aeruginosa Biofilm, Julianne M. Thornton, Jean Walker, Prem Yugandhar Kadiyam Sundarasivarao, Bernd Spur, Ana Rodriguez, Kingsley Yin

Rowan-Virtua Research Day

Pseudomonas aeruginosa (P aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients P aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen We have previously shown that a Specialized Pro resolving Mediator ( Lipoxin A 4 (LxA 4 is a quorum sensing inhibitor which can reduce P aeruginosa virulence In this study, we examined the direct actions of LxA 4 and RvD 2 on P aeruginosa biofilm formation and virulence gene expression The influence of LxA 4 on antibiotic efficacy and the combined effects on biofilm …

Evaluation Of A Keratin 1 Targeting Peptide-Doxorubicin Conjugate In A Mouse Model Of Triple-Negative Breast Cancer, Azam Saghaeidehkordi, Shiuan Chen, Sun Yang, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with a poor prognosis. While chemotherapeutics are potent, these agents lack specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies for TNBC treatment could lead to more safe and efficacious drugs. We previously engineered a breast cancer cell targeting peptide 18-4 that specifically binds cell surface receptor keratin 1 (K1) on breast cancer cells. A conjugate of peptide 18-4 and doxorubicin (Dox) containing an acid-sensitive hydrazone linker showed specific toxicity toward TNBC cells. Here, we report the …

Apigenin And Structurally Related Flavonoids Allosterically Potentiate The Function Of Human Α7-Nicotinic Acetylcholine Receptors Expressed In Sh-Ep1 Cells, Waheed Shabbir, Keun-Hang Susan Yang, Bassem Sadek, Murat Oz

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Phytochemicals, such as monoterpenes, polyphenols, curcuminoids, and flavonoids, are known to have anti-inflammatory, antioxidant, neuroprotective, and procognitive effects. In this study, the effects of several polyhydroxy flavonoids, as derivatives of differently substituted 5,7-dihydroxy-4H-chromen-4-one including apigenin, genistein, luteolin, kaempferol, quercetin, gossypetin, and phloretin with different lipophilicities (cLogP), as well as topological polar surface area (TPSA), were tested for induction of Ca²⁺ transients by α7 human nicotinic acetylcholine (α7 nACh) receptors expressed in SH-EP1 cells. Apigenin (10 μM) caused a significant potentiation of ACh (30 μM)-induced Ca²⁺ transients, but did not affect Ca²⁺ transients induced by high K^{+ …}

Computational Design Of Β-Fluorinated Morphine Derivatives For Ph-Specific Binding, Nayiri Alexander, Makena Augenstein, Angelina Sorensen, Matthew Gartner

Student Scholar Symposium Abstracts and Posters

Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pKa of the biochemically-active amine group can promote selective binding in the more acidic conditions of inflamed tissue and reduce harmful side effects associated with opioids. Herein, we explore the impact of fluorination on the pKa of fluoromorphine derivatives to identify which will bind selectively in inflamed tissue. Theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory to calculate the ΔGaq" …

Compounded Gabapentin For Felines: Associated Metabolic Processes And Analysis Of Potency, Johnny Altwal

Student Scholar Symposium Abstracts and Posters

Pharmaceutical compounding provides pharmacists and clinicians the opportunity to create unique drug formulations that are better suited to a specific patient’s needs. This is especially prevalent in veterinary medicine where clinicians treat a variety of maladies in a large number of species, thereby requiring unique formulations to more easily deliver drugs to animals. Several examples of compounded veterinary formulations with sub-therapeutic potencies have been published, but none examine compounded gabapentin. Gabapentin is frequently compounded into an oral suspension for veterinary use from tablets or capsules for the purpose of pain management in felines and other small animals. The project’s goals …

Ciliary Extracellular Vesicles Are Distinct From The Cytosolic Extracellular Vesicles, Ashraf M. Mohieldin, Rajasekharreddy Pala, Richard Beuttler, James J. Moresco, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Extracellular vesicles (EVs) are cell‐derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid‐shear flow, but many proteins encapsulated in these vesicles have never been identified. Primary cilia are ubiquitous mechanosensory organelles that protrude from the apical surface of almost all human cells. Primary cilia also serve as compartments for signalling pathways, and their defects have been associated with a wide range of human genetic diseases called ciliopathies. To better understand the mechanism of ciliopathies, it is imperative to know …

Suppression Of Human Coronavirus 229e Infection In Lung Fibroblast Cells Via Rna Interference, Hamidreza Montazeri Aliabadi, Jennifer Totonchy, Parvin Mahdipoor, Keykavous Parang, Hasan Uludağ

Pharmacy Faculty Articles and Research

Despite extensive efforts to repurpose approved drugs, discover new small molecules, and develop vaccines, COVID-19 pandemic is still claiming victims around the world. The current arsenal of antiviral compounds did not perform well in the past viral infections (e.g., SARS), which casts a shadow of doubt for use against the new SARS-CoV-2. Vaccines should offer the ultimate protection; however, there is limited information about the longevity of the generated immunity and the protection against possible mutations. This study uses Human Coronavirus 229E as a model coronavirus to test the hypothesis that effective delivery of virus-specific siRNAs to infected cells will …

Study Of Potential Drug For Alzheimer’S Disease: Small Organic Molecules, 1,5-Dhn And Tmpyp Inhibit Amyloid-Β Peptide Aggregation And Quench Hydroxyl Radicals, Matthew Murphy

Undergraduate Research Conference

Alzheimer disease (AD) is recognized as the six leading cause of the death in the United States. As of now, there is no cure for this fatal disease. The current treatment methods can only temporarily slow the worsening of symptoms. Research data suggested that an excess generation of hydroxyl radical in the brain causing the aggregation of Amyloid-β (Aβ) peptide which is considered to be responsible for Alzheimer's disease. Thus, there is a pressing need to find a suitable drug which can quench hydroxyl radicals effectively and stop or slow down the formation of aggregation of Aβ peptide. The primary …

A Novel Molecular And Cellular Study On Curcumin, Khang Nguyen

Undergraduate Research Conference

Since the discovery of G-quartet (G4)by M. Gellertin 1962, much attention has been given on G4and C4(also called i-motif) as important drug design targets for the treatment of various human disorders. G4 forming sequences are prevalent in human genome, which includes many important regions of the eukaryotic genome, such as telomere ends, regulatory regions of many oncogenes c-kit, proto-oncogene c-myc, Kirsten rat sarcoma viral oncogene homolog (KRas). Curcumin(diferuloylmethane), an antiinflammatory and antioxidant compound, is found in the rhizomes of the plant Curcuma longa. The phytopolyphenolic chemical curcumin has been in the prominence due to its diverse pharmacological activities. Here, we …

C38: Exploring Doxorubicin-Mediated Hypertrophy And Cell Death In Primary Human Cardiomyocytes, Sonia Phan

Annual Research Symposium

No abstract provided.

Development Of Miriplatin-Loaded Nanoparticles Against Non-Small Cell Lung Cancer, Zhongyue Yuan, Zizhao Xu, Xin Guo

Graduate and Professional Student Research Showcase

Lung cancer claims the highest mortality and the second-most new cases among all oncological diseases. NSCLC accounts for approximately 85% of all newly diagnosed lung cancers. Although platinum-based drugs are standard first-line chemotherapy for stage IIIB/IV NSCLC, accumulating reports have shown the failure of conventional platinum-based regimens due to drug resistance. Miriplatin is a lipophilic anti-cancer drug that has been approved in Japan for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can encapsulate anti-cancer drugs to improve their water solubility and bioavailability.

Effects Of Strong Oxidants Present In Acer Spp. On Hemolysis Methemoglobin Production In Equine Erythrocytes, Gabrielle Mcgeorge, Jeffrey Lehman

Undergraduate Honors Thesis Projects

Maple toxicosis is a deadly condition affecting equines after they have ingested wilted leaves of the genus Acer (i.e., maple species). It is characterized by hemolytic anemia and methemoglobinemia. Although the toxins responsible for causing toxicosis have not been identified, they are thought to be strong oxidants. The objective of this study is to determine the effect of eight compounds (galloyl derivatives) found in Acer spp. on hemolysis and methemoglobin production in bioassays with equine erythrocytes. Seven of the compounds are known constituents of Acer spp. that are commercially available. One of the compounds--acertannin--was isolated and characterized from leaf extracts …

Methamphetamine-Induced Changes In Myocardial Gene Transcription Are Sex-Dependent, Hasitha Chavva, Daniel A. Brazeau, James Denvir, Donald A. Primerano, Jun Fan, Sarah L. Seeley, Boyd R. Rorabaugh

Pharmaceutical Science and Research

Background: Prior work demonstrated that female rats (but not their male littermates) exposed to methamphetamine become hypersensitive to myocardial ischemic injury. Importantly, this sex-dependent effect persists following 30 days of subsequent abstinence from the drug, suggesting that it may be mediated by long term changes in gene expression that are not rapidly reversed following discontinuation of methamphetamine use. The goal of the present study was to determine whether methamphetamine induces sex-dependent changes in myocardial gene expression and whether these changes persist following subsequent abstinence from methamphetamine.

Results: Methamphetamine induced changes in the myocardial transcriptome were significantly greater in female hearts …

Pharmacological Blockade Of The 20-Hete Receptor Lowers Blood Pressure And Alters Vascular Function In Mice With Vascular Smooth Muscle- Specific Overexpression Of Cyp4a12-20-Hete Synthase, Kevin Agostinucci

NYMC Student Theses and Dissertations

20-hydroxyeicosatetraenoic acid (20-HETE) is the ω-hydroxylation product of arachidonic acid catalyzed by CYP4A and 4F enzymes. 20-HETE is a vasoactive eicosanoid of the microcirculation exhibiting effects on both vascular smooth muscle cells (VSMC) and endothelial cells (EC). In VSMCs, 20-HETE’s bioactions include the stimulation of contraction, migration, and growth. In ECs, elevated 20-HETE is associated with reduced nitric oxide (NO) bioavailability, increased angiotensin converting enzyme (ACE) expression, and the promotion of inflammation. Recently in our laboratory, we identified GPR75 as a novel target of 20-HETE that promotes changes in blood pressure and vascular function. The aim of this study is …

Data For "Subtype-Selective Positive Modulation Of Sk Channels Depends On The Ha/Hb Helices", Miao Zhang, Meng Cui

Pharmacy Faculty Data Sets

In the activated state of small-conductance Ca²⁺-activated potassium (SK) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates SK2a and SK3 channel activity but not the SK1 and IK subtypes. Here, we report that the subtype-selectivity of CyPPA relies on the HA/HB helices. Mutating residues in the HA (V420) and HB (K467) helices of SK2a channels to their equivalent residues in IK channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant IK channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the SK2a channels …

Drug Repositioning Based On Centrality Measures Of Drug Side Effects Network, Keng Ying Ying

Student Works (2020-2029)

Drug repositioning, the process of discovering new therapeutic uses of existing drugs, is an alternative to the risky, costly, and time-consuming traditional drug discovery process. Based on the hypothesis that drugs with similar side effects may share similar therapeutic indications, a network of drugs is constructed based on their side-effect similarities. Then, for a target disease of concern, the potential drug candidates that may be repurposed for treating it can be identified from among the network neighbors of the existing drugs approved for the disease. By applying three classic centrality measures – degree, closeness, and betweenness – to rank the …

Categorization Of Marketed Artificial Tear Formulations Based On Their Ingredients: A Rational Approach For Their Use, Avani Kathuria, Kiumars Shamloo, Vishal Jhanji, Ajay Sharma

Pharmacy Faculty Articles and Research

Dry eye disease is a common ocular condition affecting millions of people worldwide. Artificial tears are the first line therapy for the management of dry eye disease. Artificial tear formulations contain a variety of active ingredients, biologically active excipients, and preservatives. Many of these formulations are also available as preservative-free. This study was conducted to inspect artificial tear formulations currently marketed in the United States for their active ingredients, biologically relevant excipients, and preservatives. The marketed artificial tears were examined at various US retail pharmacy chains and using the manufacturers’ website to compile information about active ingredients, inactive ingredients, and …

Anti‑Estrogenic And Anti‑Aromatase Activities Of Citrus Peels Major Compounds In Breast Cancer, Maha Salama, Dina Mahmoud Elkersh, Shahira M. Ezzat, Yasmeen Attiaa, Engy A. Mahrous, Mohey Elmazar

Pharmacy

Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC50s and were therefore selected for further assays. In silico molecular modeling …

N-Nitrosodimethylamine (Ndma) Contamination Of Ranitidine Products: A Review Of Recent Findings, Fahad S. Aldawsari, Yahya M. Alshehri, Thamer S. Alghamdi

Journal of Food and Drug Analysis

Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, we review and discuss the results of the United States Food and Drug Administration and the Australian Therapeutic Goods Administration laboratory testing of ranitidine products and the detected NDMA levels. Finally, …