Medicinal and Pharmaceutical Chemistry Commons^™

Cyclic Peptides With Antifungal Properties Derived From Bacteria, Fungi, Plants, And Synthetic Sources, Naiera M. Helmy, Keykavous Parang

Pharmacy Faculty Articles and Research

Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal peptides, have been in development as potential antifungal agents since 1948. In recent years, there has been growing attention from the scientific community to explore cyclic peptides as a promising strategy for combating antifungal infections caused by pathogenic fungi. The identification of antifungal cyclic peptides from various sources has been possible due to the widespread interest in …

Alcohol As A Modifiable Risk Factor For Alzheimer’S Disease—Evidence From Experimental Studies, Devaraj V. Chandrashekar, Ross A. Steinberg, Derick Han, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment and memory loss. Epidemiological evidence suggests that heavy alcohol consumption aggravates AD pathology, whereas low alcohol intake may be protective. However, these observations have been inconsistent, and because of methodological discrepancies, the findings remain controversial. Alcohol-feeding studies in AD mice support the notion that high alcohol intake promotes AD, while also hinting that low alcohol doses may be protective against AD. Chronic alcohol feeding to AD mice that delivers alcohol doses sufficient to cause liver injury largely promotes and accelerates AD pathology. The mechanisms by which alcohol can …

Design, Synthesis, And Antiproliferative Activity Of Benzopyran-4-One-Isoxazole Hybrid Compounds, Shilpi Gupta, Shang Eun Park, Saghar Mozaffari, Bishoy El-Aarag, Keykavous Parang, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds 5a–d displayed significant antiproliferative activities against all the cancer cell lines tested, and IC₅₀ values were in the range of 5.2–22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC₅₀ values of 5a–d …

Development And Validation Of An Ultrahigh-Performance Liquid Chromatography–Tandem Mass Spectrometry 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 …

The Opioid Epidemic: How Genetics Play A Role In Addiction And Treatment, Kirsten Houston

Honors College Theses

The opioid epidemic is an issue within the pharmaceutical industry in the United States of America due to prescription and non-prescription substances being made available to the population. Opioids include chemical substances that affect the body and brain through opioid receptors, including the mu, kappa, and delta receptors. These substances are derived and synthesized from the poppy plant. Multiple causes have been linked to opioid abuse disorder, including but not limited to employment, income, housing, nutrition, mental health disorders, and genetics. By gathering information from previous literature, genetics may be the main cause of narcotic analgesic tolerance and abuse. Specific …

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 …

Isolated Temazepam Overdose: A Unique Case Of An Unresponsive Female, Eric Doane

Rowan-Virtua Research Day

Cases of acute overdose presenting to the emergency department pose a great challenge given that history can sometimes be limited or at times be inaccurate. While naloxone is routinely given in the field to help reduce opiate’s sedating effects, the routine use of flumazenil has not been routinely adopted in cases of benzodiazepine overdose. This is because, unlike naloxone, there are many medications that act on the GABA receptor, and flumazenil is only specific for binding to the benzodiazepine/GABA receptor. This can lead to an unmasking of other medications that may be co-ingested that also effect the GABA receptor leading …

Genetic Mutations Of KCa2.3 And KCa3.1 Channels Affect Ca2+ Sensitivity, Razan Orfali

Pharmaceutical Sciences (PhD) Dissertations

The Ca²⁺-activated potassium channels K_Ca channels are a unique family of potassium channels activated by intracellular calcium. K_Ca channels are critical for maintaining K⁺ homeostasis and modulate several physiological processes, from the firing properties of neurons to the control of the transmitter release. The Ca²⁺ sensitivity of these channels allows intracellular Ca²⁺ to regulate the electrical activity of the cell membrane. Increased Ca²⁺ sensitivity of K_Ca channels caused by gain of function mutations (GOF) in the KCNN genes results in a broad spectrum of human channelopathies, including Zimmermann- Laband syndrome (ZLS), …

Synthesis Of Ferrous Fumarate From Indonesian Iron Sand And In Vivo Body Weight Gain Test In Rats, Taufiq Indra Rukmana, Felicia Natalia Kurniadi, Harmita Harmita

Pharmaceutical Sciences and Research

Iron deficiency anemia (IDA) is a health problem in Indonesia. Prevention and treatment of IDA is carried out by giving fortified foods and oral iron therapy. Both can use ferrous fumarate which is made with reacting bivalent iron and disodium fumarate. Bivalent iron can be obtained from iron sand in Indonesia. This study aims to synthesize ferrous fumarate from Indonesian iron sand, which is from Malang, Sukabumi, and Cianjur area, and to determine its absorption through in vivo body weight gain test in male Wistar white rats (Rattus norvegicus). First, ferrous fumarate was synthesized through reaction of ferrous …

Anti-Factor Xa Level Monitoring For Enoxaparin Prophylaxis And Treatment In High-Risk Patient Groups, Lucie Sikes, Kipson Charles, Abigail Antigua, Rima Patel, Selina Imboywa, Pheba Cherian

HCA Healthcare Journal of Medicine

Monitoring anti-factor Xa levels is a controversial topic in the inpatient setting due to resource utilization and unclear conditional guideline recommendations regarding this practice. Enoxaparin dosing in certain high-risk patient populations such as those with low body weight, obesity, renal insufficiency, and pregnancy has not been determined. The objective of this review was to assess the safety and efficacy of enoxaparin monitoring via anti-factor Xa levels in high-risk patient populations.

The PubMed database was searched for articles related to low-molecular-weight heparin monitoring. Randomized controlled trials and meta-analyses that evaluated the safety and efficacy of enoxaparin prophylaxis and treatment in patients …

Testing Of Indazole Inhibitors Of Kasa, A Vital Enzyme Of M. Tuberculosis, Karissa Highlander

Student Research Submissions

Tuberculosis is a disease that affects the lungs caused by Mycobacterium tuberculosis (M. tuberculosis). Although drug treatment options exist, increased rates of antibiotic resistant strains have become more prevalent in recent years, driving a need for new treatment approaches. KasA, a β-ketoacyl synthase, has been found to synthesize parts of the cell wall and been identified as an attractive drug target. Previous medicinal chemistry research has been completed to synthesize six effective competitive inhibitors of KasA that would potentially block the enzyme from binding the substrate, preventing elongation of the backbone and creation of the mycolic fatty acids that …

Keynote Speaker Arkansas Women In Stem Conference Presentation, Maria Ines Ines Dow

Arkansas Women in STEM Conference

The Keynote Speaker of the 3rd Annual Arkansas Women in STEM Conference is Dr. Diana Escalona-Vargas, Assistant Professor of Pediatrics at UAMS and ACH, and Scientific Director of the Arkansas Children's Hospital Magnetoencephalography Laboratory.

Effects Of Cannabichromene On Pain And Neuroinflammation In Hiv-1 Tat Transgenic Mice, Sydney Wheeler

Honors Theses

HIV-1 TransActivator of Transcription (Tat) is a vital regulatory protein involved in HIV replication and implicated in development of HIV-associated pain and neurocognitive deficits. Tat is thought to contribute to these pathologies through proinflammatory pathways. Developing mechanisms to curb Tat-mediated inflammation is a key step in improving the quality of life of those living with HIV. Both recreational and medicinal cannabis use is prevalent among many people living with HIV; given this prevalence and the perceived anti-inflammatory benefits of cannabis use, it is important to investigate how chemical constituents of cannabis may impact HIV. In the present study, the effects …

The Application Of Continuous Stationary Phase Gradients To High-Performance Liquid Chromatography And Its Potential To Improve Pharmacological Research, Hannah Klose

Senior Honors Theses

The separation of mixtures into different components is integral to experimentation and analysis in a multitude of fields. Chromatography is one of the most popular, well-developed, and well-studied methods used to examine the makeup of a mixture. Thus, the improvement of chromatographic procedures directly benefits research across many scientific disciplines. The application of a continuous stationary phase gradient to High-Performance Liquid Chromatography (HPLC) methods has been proposed to improve the separation of complex mixtures that are difficult to achieve with existing separation techniques. By incorporating a gradient stationary phase, analysts will create a more selective mode of separation to improve …

Pyrazole-Sulfonamide Scaffold Featuring Dual-Tail Strategy As Apoptosis Inducers In Colon Cancer, Amira Khalil, Reham M. M. El Hazek, Nashwa H. Zaher, Hagar E. S. Emam, Marwa G. Elgazzar

Pharmacy

Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX (CA IX) inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of CA IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with IC₅₀s’ of 45.88, 28.27, and 16.57 uM, 25.01, 8.99, and 3.27 µM, respectively. Both compounds induced cellular apoptosis …

The Effects Of A Blood–Brain Barrier Penetrating Erythropoietin In A Mouse Model Of Tauopathy, Joshua Yang, Weijun Ou, Nataraj Jagadeesan, Juste Simanauskaite, Jiahong Sun, Demi M. Castellanos, David H. Cribbs, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; …

Various Synthetic Pathways Towards Efavirenz And Its Analogs; The Replacement Of The Side Chain, Elizabeth S. Bautista

Selected Honors Theses

Cyclopropyl acetylene (CA) is a key intermediate in the synthesis of the human immunodeficiency virus (HIV) reverse transcriptase inhibitor, Efavirenz (EFV), an antiviral drug used to treat HIV. CA is an expensive raw material, difficult to obtain, and employed in the preparation of medications to combat acquired immunodeficiency syndrome (AIDS). It was found that the structure could be synthesized by the utilization of PCl5; however, this resulted in unwanted ring opening products. To address this issue, a one pot synthesis was developed using Ph3PCl2 as a mild chlorinating agent. In addition, a new analog has been proposed substituting the cyclopropyl …

Computational Evaluation Of Bioactive Compounds From Vaccinium Vitis-Idaea L (Ligonberry) For Treating Kras-Associated Lung Cancer, Ayooluwa Ilesanmi, Gbenga Dairo, Toheeb Balogun, Bibiire Awoyale

Undergraduate Research Conference

Lung cancer is the cancer of the lung's epithelial cells typically characterized by difficult breathing, chest pain, blood-stained coughs, headache, and weight loss. If left unmanaged, lung cancer can spread to other body parts. While several treatment methods exist for managing lung cancer, exploring natural plant sources for developing therapeutics offers great potential in complementing different treatment approaches. In this study, we concentrated on inhibiting the mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) by targeting an associated protein (Phosphodiesterase 6δ) to which KRAS form complexes. We evaluated bioactive compounds from Lingonberry (Vaccinium vitis-idaea L), adopting computational approaches such as …

Debunking Old Evolution Theories, Proposing New One (Near Neutral Balanced Selection Theory/Nnbst) Using Sars Cov 2 Genomic Data, Chun Wu

Faculty Scholarship for the College of Science & Mathematics

The COVID 19 pandemic has caused 672 million infections and 6 million deaths understanding the molecular evolution of this virus is critical to ending this pandemic • The SARS CoV 2 genome exhibits a time independent, constant genomic substitution rate ( despite increasing vaccinations and infected human cases (Figure 1 A) • Out of the three main evolutionary theories S electionist Theory/ST, Kimura’s Neutral Theory/KNT, Ohta’s Nearly Neutral Theory/ONNT), the SARS CoV 2 GSR seemingly follows KNT but this does not explain the critical intervention by vaccines and therapeutic drugs on the evolution of this virus I n this study …

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 …

Amphiphilic Cell-Penetrating Peptides Containing Arginine And Hydrophobic Residues As Protein Delivery Agents, Jonathan Moreno, Khalid Zoghebi, David Salehi, Lois Kim, Sorour Khayyatnejad Shoushtari, Rakesh K. Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic–linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]4, [WR]9, [WWRR]4, [WWRR]5, [(RW)5K](RW)5, [R5K]W7, and [DipR]5. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal …

Responsiveness Of Higher Education Programs To Policy And Recommendations In The Biopharmaceutical Sector, Maeve Scott

Other resources

This essay will review the business and government policies relevant to the biopharmaceutical sector which influence higher education programs. The mechanisms which enable higher education to adapt to policy will be summarised and the pace of the response estimated.

Higher education (HE) programs need to respond in a timely manner to dynamic industries to maximise opportunities for graduates and support the Irish economy. The author manages internships and teaches on pharmaceutical science programs and aims to ensure the program is current to maximise student success. This review intends to identify the most relevant policy sources that can inform the Pharmaceutical …

Quantitative Phosphoproteomic Analysis Reveals Unique Camp Signaling Pools Emanating From Ac2 And Ac6 In Human Airway Smooth Muscle Cells, Isabella Cattani-Cavalieri, Yue Li, Jordyn Margolis, Amy S. Bogard, Moom R. Roosan, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Human airway smooth muscle (HASM) is the primary target of ßAR agonists used to control airway hypercontractility in asthma and chronic obstructive pulmonary disease (COPD). ßAR agonists induce the production of cAMP by adenylyl cyclases (ACs), activate PKA and cause bronchodilation. Several other G-protein coupled receptors (GPCR) expressed in human airway smooth muscle cells transduce extracellular signals through cAMP but these receptors elicit different cellular responses. Some G-protein coupled receptors couple to distinct adenylyl cyclases isoforms with different localization, partly explaining this compartmentation, but little is known about the downstream networks that result. We used quantitative phosphoproteomics to define the …

Development Of A Method For Identifying And Quantifying Epicatechin In Cinnamon Extract Supplement Capsules, Danielle Valls

Annual Research Symposium

No abstract provided.

A Ligand-Based Approach To Identifying Commercially Available Inhibitors Of Human Galactokinase (Galk), Tyler Rose

Annual Research Symposium

The purpose of this project was to find inhibitors of the human galactokinase (GALK) enzyme. GALK is responsible for catalyzing the conversion of galactose to galactose 1-phosphate, the first step in galactose metabolism. Galactose 1-phosphate builds up in the cells of patients with type 1 galactosemia due a genetic disorder. It has been proposed that inhibiting galactose 1-phosphate production by GALK may prevent many of the major complications of type 1 galactosemia. In this study, a ligand-based approach was used to identify commercially available inhibitors of GALK, starting from galactose-bearing natural products. Candidate inhibitors were screened for their ability to …

Modified Linear Peptides Effectively Silence Stat-3 In Breast Cancer And Ovarian Cancer Cell Lines, Dindyal Mandal, Sandeep Lohan, Muhammad Imran Sajid, Abdulelah Alhazza, Rakesh Kumar Tiwari, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

RNA interference (RNAi) has drawn enormous attention as a powerful tool because of its capability to interfere with mRNA and protein production. However, designing a safe and efficient delivery system in RNAi therapeutics remains challenging. Herein, we have designed and synthesized several linear peptides containing tryptophan (W) and arginine (R) residues separated by the β-alanine (βA) spacer and attached to a lipophilic fatty acyl chain, cholesterol, or PEG. The peptide backbone sequences were: Ac-C-βA-βA-W4-βA-βA-R4-CO-NH2 and Ac-K-βA-βA-W4-βA-βA-R4-CO-NH2, with only a difference in N-terminal amino acid. The cysteine side chain in the first sequence was used for the conjugation with PEG2000 and …

Predicting Survival Of Nsclc Patients Treated With Immune Checkpoint Inhibitors: Impact And Timing Of Immune-Related Adverse Events And Prior Tyrosine Kinase Inhibitor Therapy, Michael R. Sayer, Isa Mambetsariev, Kun-Han Lu, Chi Wah Wong, Ashley Duche, Richard Beuttler, Jeremy Fricke, Rebecca Pharaon, Leonidas Arvanitis, Zahra Eftekhari, Arya Amini, Marianna Koczywas, Erminia Massarelli, Moom Rahman Roosan, Ravi Salgia

Pharmacy Faculty Articles and Research

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined.

Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs.

Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI …

Challenging Breast Cancer Through Novel Sulfonamide–Pyridine Hybrids: Design, Synthesis, Carbonic Anhydrase Ix Inhibition And Induction Of Apoptosis., Amira Khalil, Nashwa H. Zaher, Reham Mm Elhazek, Ahmed E. Gouda, Marwa G. Elgazzar

Pharmacy

Background: Among the important key modulators of the tumor microenvironment and hypoxia is a family of enzymes named carbonic anhydrases. Herein, 11 novel sulfonamide–pyridine hybrids (2–12) were designed, synthesized and biologically evaluated for their potential use in targeting breast cancer. Methods & results: The para chloro derivative 7 reported the highest cytotoxic activity against the three breast cancer cell lines used. In addition, compound 7 was found to induce cell cycle arrest and autophagy as well as delaying wound healing. The IC50 of compound 7 against carbonic anhydrase IX was 253 ± 12 nM using dorzolamide HCl as control. Conclusion: …

A Critical Appraisal Of The Physicochemical Properties And Biological Effects Of Artificial Tear Ingredients And Formulations, Judy Weng, Michael K. Fink, Ajay Sharma

Pharmacy Faculty Articles and Research

Dry eye disease is among the most prevalent diseases affecting the ocular surface. Artificial tears remain the cornerstone therapy for its management. There are currently a wide variety of marketed artificial tears available to choose from. These artificial tears differ significantly in their composition and formulation. This article reviews the physicochemical and biological properties of artificial tear components and how these characteristics determine their use and efficacy in the management of dry eye. Furthermore, this article also discusses the various formulations of artificial tears such as macro and nanoemulsion and the type of preservatives present in them.

Loss-Of-Function KCa2.2 Mutations Abolish Channel Activity, Young-Woo Nam, Mohammad Asikur Rahman, Grace Yang, Razan Orfali, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) are operated exclusively by a Ca²⁺-calmodulin gating mechanism. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders including cerebellar ataxia and tremor in humans and rodents. Taking advantage of these pathogenic mutations, we performed structure-function studies of the rat K_Ca2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic K_Ca2.2 mutants. When co-expressed with the K_Ca2.2_WT channel, mutations of the pore-lining amino acid residues (I360M, Y362C, G363S …