Medicinal and Pharmaceutical Chemistry Commons^™

Ozgene: To Advance Humanity – Inspire Curiosity, Maarit Patrick, Mike Dixon

Huntsman School of Business Teaching Scholarship Series

The case introduces the students to Ozgene, an Australian firm that experienced a dramatic reduction in lead time of their products because of implementation of Lean principles. The case can be used in undergraduate or graduate courses in operations management or supply chain management as an introduction to Lean principles. The case also encourages students to consider the challenges that make-to-order differ from those of make-to-stock and explore production design principles.

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Piperine Encourages Apoptosis In Human Cervical Adenocarcinoma Cells Through Ros Generation, Dna Fragmentation, Caspase-3 Activation And Cell Cycle Arrest, Asif Jafri, Juhi Rais, Sudhir Kumar, Md Arshad

Research Symposium

Background: Cancer is one of the most common destructive diseases and the second leading cause of death in humans. Among cancer, cervical cancer is the second most common malignancy among women globally. Thus, there is a continuous need to search for chemotherapeutic chemicals or naturally occurring drugs to resolve this global health problem. Piperine (1-piperoylpeperdine) is present in the fruits of black pepper (Piper nigrum Linn.) and long pepper (Piper longum Linn.). It possesses several pharmacological properties and in the present study we have evaluated its anti-cancer potential on human cervical adenocarcinoma (HeLa) cells.

Methods: The anti-proliferative effect …

Oral Dosages Of The Nsaid Aspirin Decreased The Growth Rate Of Species Found In The Human Gut Microbiome Including Akkermansia Muciniphila, Bacteroides Fragilis, Clostridium Sordellii, And Clostridium Difficile, Wyatt H. Greenbaum, Garrett J. Greenbaum, Anna Spiezio

PANDION: The Osprey Journal of Research and Ideas

Over past few decades, new insight has been revealed in the scientific community about the importance of the human gut microbiome relating to general health. It is known that imbalances in the species that reside in the human gut can cause organism-wide problems in humans. When prescribing or injecting oral medications, the thought of the downstream effects on the gut microbiome are not always considered. By exposing known healthy members of the gut; Akkermansia muciniphila, Bacteroides fragilis, Clostridium sordellii, and Clostridium difficile to the Aspirin, this study attempted to provide insight into the effects of the drug on bacterial growth. …

Design, Molecular Modelling And Synthesis Of Novel Benzothiazole Derivatives As Bcl-2 Inhibitors, Amira Khalil, Hoda S. Ismail, Dalal A. Abou El Ella, Deena S. Lasheen, Rabah A. Taha

Pharmacy

Apoptosis plays a crucial role in cancer pathogenesis and drug resistance. BCL-2 family of enzymes is considered as one of the key enzymes which is involved in apoptosis. When there is disruption in the balance between anti-apoptotic and pro-apoptotic members of the BCL-2 family apoptosis is dysregulated in the affected cells. Herein, 33 novel benzothiazole-based molecules 7a-i, 8a-f, 9a-b, 12a-e, 13a-d, 14a,b, and 17a-j were designed, synthesized and tested for their BCL-2 inhibitory activity. Scaffold hopping strategy was applied in designing of the target compounds. Compounds 13c and 13d showed the highest activity with IC50 values equal to 0.471 and …

Structural Features Of Thyroglobulin Linked To Protein Trafficking, Cintia E. Citterio, Kookjoo Kim, Bhavana Rajesh, Kevin Pena, Oliver Biggs Clark, Peter Arvan

Pharmacy Faculty Articles and Research

Thyroglobulin must pass endoplasmic reticulum (ER) quality control to become secreted for thyroid hormone synthesis. Defective thyroglobulin, blocked in trafficking, can cause hypothyroidism. Thyroglobulin is a large protein (~2750 residues) spanning regions I–II–III plus a C-terminal cholinesterase-like domain. The cholinesterase-like domain functions as an intramolecular chaperone for regions I–II–III, but the folding pathway leading to successful thyroglobulin trafficking remains largely unknown. Here, informed by the recent three-dimensional structure of thyroglobulin as determined by cryo-electron microscopy, we have bioengineered three novel classes of mutants yielding three entirely distinct quality control phenotypes. Specifically, upon expressing recombinant thyroglobulin, we find that first, mutations …

Anti-Inflammatory And Antioxidant Effects Of Sea Urchin Spine Extract, Dina Magdy El Gamal

The Undergraduate Research Journal

Diadema savignyi spine extract in an experimental setup using L929 cell line in vitro. The cell metabolic activity of L929 cells is tested through an MTT assay. The sea urchin spine extract is applied to the cells in two concentrations: 100 μg/ml (136% viability) and 200 μg/ml (95% viability). The bioactive components of the sea urchin spine are identified via GC-MS, and the antioxidant and anti-inflammatory activities are evaluated using catalase assay (CAT), glutathione (GSH), and nitric oxide (NO) tests. Results show that the GC-MS identified bioactive components including the anti-inflammatory and anti-irritant bisabolol oxide and the pro-inflammatory oleic acid. …

Probing The Activation Mechanisms Of Agonist Dpi-287 To Delta-Opioid Receptor And Novel Agonists Using Ensemble-Based Virtual Screening With Molecular Dynamics Simulations., Emily Dean, Annemarie Dominique, Americus Palillero, Annie Tran, Nicholas Paradis, Chun Wu

College of Science & Mathematics Departmental Research

Pain drugs targeting mu-opioid receptors face major addiction problems that have caused an epidemic. The delta-opioid receptor (DOR) has shown to not cause addictive effects when bound to an agonist. While the active conformation of the DOR in complex with agonist DPI-287 has been recently solved, there are still no FDA-approved agonists targeting it, providing the opportunity for structure-based virtual screening. In this study, the conformational plasticity of the DOR was probed using molecular dynamics (MD) simulations, identifying two representative conformations from clustering analysis. The two MD conformations as well as the crystal conformation of DOR were used to screen …

Isatin-Pyrimidine Hybrid Derivatives As Enoyl Acyl Carrier Protein Reductase (Inha) Inhibitors Against Mycobacterium Tuberculosis, Amira Khalil, Samy Mohamady, Amgad Albohy, Marwa M. Abdel-Aziz, Abdalrahman Khalifa

Pharmacy

Tuberculosis is a worldwide problem that impose a burden on the economy due to continuous development of resistant strains. The development of new antitubercular drugs is a need and can be achieved through inhibition of druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein (ACP) reductase (InhA) is an important enzyme for Mycobacterium tuberculosis survival. In this study, we report the synthesis of isatin derivatives that could treat TB through inhibition of this enzyme. Compound 4l showed IC50 value (0.6 ± 0.94 µM) similar to isoniazid but is also effective against MDR and XDR Mycobacterium tuberculosis strains (MIC of 0.48 and …

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 …

Targeting Breast Cancer: The Familiar, The Emerging, And The Uncharted Territories, Hamidreza Montazeri Aliabadi, Arthur Manda, Riya Sidgal, Co Chung

Pharmacy Faculty Articles and Research

Breast cancer became the most diagnosed cancer in the world in 2020. Chemotherapy is still the leading clinical strategy in breast cancer treatment, followed by hormone therapy (mostly used in hormone receptor-positive types). However, with our ever-expanding knowledge of signaling pathways in cancer biology, new molecular targets are identified for potential novel molecularly targeted drugs in breast cancer treatment. While this has resulted in the approval of a few molecularly targeted drugs by the FDA (including drugs targeting immune checkpoints), a wide array of signaling pathways seem to be still underexplored. Also, while combinatorial treatments have become common practice in …

Nanoformulations Of Essential Oils Extracted From Pistacia Lentiscus And Boswellia Sacra And Investigation Of Their Anticancer, Antimicrobial, And Antioxidant Activities., Obaydah Abd Alkader Alabrahim

Theses and Dissertations

Essential oils (EOs) obtained from natural sources have shown promising biological and therapeutical properties such as anticancer, antimicrobial, and antioxidant activities, attributing to their high content of a variety of bioactive components. However, EOs’ therapeutic properties are limited by their low stability, poor bioavailability, high volatility, and low targeting ability. Therefore, the encapsulation and nanoformulation of EOs can maximize their therapeutical efficiency and physicochemical properties while overcoming their undesirable side effects and drawbacks. EOs extracted from the resins of Pistacia Lentiscus var. Chia (P.oil) and Boswellia Sacra (B.oil) are two promising EOs that have shown great therapeutic potential. P.oil was …

Encephalopathy Tango: When Beta-Lactam Antibiotics Waltz With Gaba Receptor, Ali Mohamed, Nagesh Jadhav, Mohamed Elbathani, Abubaker Farah

Advances in Clinical Medical Research and Healthcare Delivery

Beta-lactam antibiotics are a class of drugs that are widely used to treat a variety of infections. They are generally well-tolerated, but they can cause a variety of side effects, including allergic reactions, acute interstitial nephritis (AIN) and neurotoxicity.

We present a patient who developed neurotoxicity after being treated with cephalosporin and carbapenem antibiotics. A 76-year-old female was admitted to the hospital with osteomyelitis of the right foot. She was initially treated with cefepime and daptomycin. She was discharged and then began to experience delirium with visual hallucinations and acute kidney injury. After common causes of confusion were excluded, the …

Design And Synthesis Of Small Molecule Drugs For Cns Disorders, Kirsten T. Tolentino

Theses & Dissertations

Dopamine (DA) is an important neurotransmitter for the regulation and long-term function of the central nervous system (CNS). DA binds to Dopamine Receptors (DR) to stimulate or inhibit adenyl cyclase production to further elicit a pharmacological response. DRs were cloned, and it was determined that there are two families separated by their function and five total subtypes distinguished by their amino acid structure. The Dopamine 4 receptor (D4R) is the second least studied subtype but has high expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, and thalamus. Dopamine signaling and transmission, especially in the …

Design, Synthesis, And Evaluation Of Novel Peptidomimetics As Neurolysin Activators For The Treatment Of Ischemic Stroke., Md. Shafikur Rahman

Theses & Dissertations

Stroke is the world's second-leading cause of death and disability. Ischemic stroke (IS), a primary subtype of stroke, has ineffective and limited treatment options, resulting in a significant unmet medical need for novel therapies. Tissue plasminogen activator (tPA) is the sole FDA-approved medication now in use; however, it has a narrow therapeutic window (3 to 4.5 h). Unfortunately, few individuals have this opportunity to be diagnosed with stroke in time to begin therapy with tPA. Additionally, treatment with tPA can have major adverse effects, such as bleeding, which can exacerbate the consequences of a stroke on the brain. To overcome …

Α7 Nicotinic Acetylcholine Receptor Interaction With G Proteins In Breast Cancer Cell Proliferation, Motility, And Calcium Signaling, Murat Oz, Justin R. King, Keun-Hang Susan Yang, Sarah Khushaish, Yulia Tchugunova, Maitham A. Khajah, Yunus A. Luqmani, Nadine Kabbani

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Chronic smoking is a primary risk factor for breast cancer due to the presence of various toxins and carcinogens within tobacco products. Nicotine is the primary addictive component of tobacco products and has been shown to promote breast cancer cell proliferation and metastases. Nicotine activates nicotinic acetylcholine receptors (nAChRs) that are expressed in cancer cell lines. Here, we examine the role of the α7 nAChR in coupling to heterotrimeric G proteins within breast cancer MCF-7 cells. Pharmacological activation of the α7 nAChR using choline or nicotine was found to increase proliferation, motility, and calcium signaling in MCF-7 cells. This effect …

Proteoglycan 4 (Prg4)/Lubricin And The Extracellular Matrix In Gout, Khaled A. Elsaid, Gregory D. Jay, Ru Liu-Bryan, Robert Terkeltaub

Pharmacy Faculty Articles and Research

Proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes, released into synovial fluid, and adsorbed on cartilage and synovial surfaces. PRG4′s roles include cartilage boundary lubrication, synovial homeostasis, immunomodulation, and suppression of inflammation. Gouty arthritis is mediated by monosodium urate (MSU) crystal phagocytosis by synovial macrophages, with NLRP3 inflammasome activation and IL-1β release. The phagocytic receptor CD44 mediates MSU crystal uptake by macrophages. By binding CD44, PRG4 limits MSU crystal uptake and downstream inflammation. PRG4/CD44 signaling is transduced by protein phosphatase 2A, which inhibits NF-κB, decreases xanthine oxidoreductase (XOR), urate production, and ROS-mediated IL-1β …

KCa2 And KCa3.1 Channels In The Airways: A New Therapeutic Target, Razan Orfali, Ali Alfaiz, Mohammad Asikur Rahman, Liz Lau, Young-Woo Nam, Miao Zhang

Pharmacy Faculty Articles and Research

K⁺ channels are involved in many critical functions in lung physiology. Recently, the family of Ca²⁺-activated K⁺ channels (K_Ca) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of K_Ca channels, three small-conductance Ca²⁺-activated K⁺ (K_Ca2) channel subtypes, together with the intermediate-conductance K_Ca3.1 channel, are voltage-independent K⁺ channels, and they mediate Ca²⁺-induced membrane hyperpolarization. Many K_Ca2 channel members are involved in crucial roles in physiological and pathological …

Sirna Drug Delivery Across The Blood–Brain Barrier In Alzheimer's Disease, Muhammad Imran Sajid, Fahad Sultan Sheikh, Faiza Anis, Nourina Nasim, Rachita K. Sumbria, Surya M. Nauli, Rakesh K. Tiwari

Pharmacy Faculty Articles and Research

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a few FDA-approved drugs that provide modest symptomatic benefits and only two FDA-approved disease-modifying treatments for AD. The advancements in understanding the causative genes and non-coding sequences at the molecular level of the pathophysiology of AD have resulted in several exciting research papers that employed small interfering RNA (siRNA)-based therapy. Although siRNA is being sought by academia and biopharma industries, several challenges still need to be addressed. We comprehensively report the latest advances in AD pathophysiology, druggable targets, ongoing clinical trials, and the siRNA-based approaches across the blood–brain barrier for addressing …

Promiscuous Enzymes For Residue-Specific Peptide And Protein Late-Stage Functionalization, Ashley K. Alexander, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

The late-stage functionalization of peptides and proteins holds significant promise for drug discovery and facilitates bioorthogonal chemistry. This selective functionalization leads to innovative advances in in vitro and in vivo biological research. It is a challenging endeavor to selectively target a certain amino acid or position in the presence of other residues containing reactive groups. Biocatalysis has emerged as a powerful tool for selective, efficient and economical modifications of molecules. Enzymes that have the ability to modify multiple complex substrates or selectively install nonnative handles have wide applications. Herein, we highlight enzymes with broad substrate tolerance that have been demonstrated …