Medicinal Chemistry and Pharmaceutics Commons^™

Synthesis And Evaluation Of A Novel Carbohydrate Template And Analogs Thereof For Potential Cns-Active Drugs, Emi Hanawa-Romero

Seton Hall University Dissertations and Theses (ETDs)

Central nervous system (CNS) disorders are becoming a major societal problem. Examples of well-known CNS disorders are: neurodegenerative disorders such as Parkinson's, Huntington's and Alzheimer’s diseases, epilepsy/seizures, addiction, bipolar disorder, catalepsy, meningitis, migraines, attention deficit/hyperactivity disorder (ADHD), and multiple sclerosis. CNS disorders can be caused by various factors and therefore can affect ages, genders and races of all.

The population of patients with CNS disorders is increasing and a significant percentage of patients have symptoms that are not controlled by existing treatments. In addition, since CNS disorders are chronic disorder, there is no cure and thus the patients have to …

A Variant Pfcrt Isoform Can Contribute To Plasmodium Falciparum Resistance To The First-Line Partner Drug Piperaquine, Satish K. Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Ann N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J. Egan, David A. Fidock

Collected Faculty Scholarship

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisininbased combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nucleasebased gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ …

Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia

Theses & Dissertations

The neurotensin receptor 1 (NTR1) is overexpressed in many cancers, due to its role as a growth pathway. These NTR1-positive cancers include pancreatic, colon, prostate and breast cancers. In the radiopharmaceutical field, the overexpression of NTR1 in cancer has prompted the development of NTR1-targeted diagnostics and therapeutics. The neurotensin (NT) peptide exhibits low nanomolar affinity for NTR1 and has been the paradigm for NTR1-targeted agents. Since the 1980’s, radiolabeled NT analogs have been developed and evaluated for targeting NTR1-positive cancers. Since native NT is rapidly degraded in vivo by a variety of peptidases, a tremendous amount of effort has been …

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the …

Neurotensin Nts1 And Nts2 Receptor Agonists Produce Anxiolytic-Like Effects In The 22-Khz Ultrasonic Vocalization Model In Rats, Floyd F. Steele Iii, Shannon C. Whitehouse, Jacob S. Aday, Adam J. Prus

Journal Articles

Neurotensin is a neuropeptide neurotransmitter that interacts with multiple neurotransmitter systems, including those regulating amygdalar function, via NTS₁ and NTS₂ receptors. Both receptors are expressed in the amygdala and agonists for NTS₁ or NTS₂ receptors have exhibited anxiolytic effects in animal models. Systemic adminstration of NTS₁ receptor agonist PD149163 was recently shown to reduce footshock conditioned 22-kHz ultrasonic vocalizations in rats, suggesting that PD149163 produced an anxiolytic effect. The effects that neurotensin may have or a selective NTS₂receptor agonist may have on 22-kHz vocalizations has yet to be examined. The current study evaluated …

Survival Model Of Intrahepatic Cholangiocarcinoma; Sex As A Biological Variable, Mary A. Phillippi, Justin L. Mott, Cody J. Wehrkamp, Ying Xie, David Oupicky, Ashley M. Mohr, Bailey A. Stringham

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Approach Towards The Development Of Novel Disease Modifying Therapeutics For Parkinson's Disease, Dan Luo

Wayne State University Dissertations

Parkinson’s disease (PD) is an age-related neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous deposits named Lewy bodies (LBs) or Lewy neurites (LNs). A broad spectrum of motor and non-motor symptoms has been observed in PD, with bradykinesia, resting tremor, rigidity, and postural instability as its key clinical features. Although the etiology of PD is still not well-understood, multiple pathological factors including oxidative stress, mitochondrial dysfunction, α-synuclein (αSN) protein aggregation, as well as genetic and environmental aspects are strongly implicated in the disease …

Protein Phosphatase 2a Function And Regulation In Insulin Resistant Human Skeletal Muscle Cells, Shukurat Sulaiman

Wayne State University Theses

Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase involved in insulin signaling pathway, plays a critical role in the development of insulin resistance and type 2 diabetes (T2D), which is characterized with hyperinsulinemic hyperglycemic condition. Moreover, majority of the glucose disposal takes place in the skeletal muscle which is also the main tissue responsible for insulin resistance. The catalytic subunit of PP2A (PP2Ac) can interact with multiple regulatory subunits and other regulatory proteins as well as substrates. These interactions are important for maintain normal PP2A function and subsequent cell signaling. We hypothesized that hyperinsulinemic hyperglycemic condition and insulin stimulation would …

Salvianolic Acid B For Pulmonary Delivery Towards Reversal Of Emphysema, Sneha Dhapare

Theses and Dissertations

A new pathobiologic hypothesis has recently emerged that the alveolar structural destruction and loss in emphysema are caused by the deficiency of vascular endothelial growth factor (VEGF). Therefore, this project hypothesized that such pathobiologic VEGF deficiency of emphysematous lungs can be recovered with a natural caffeic acid tetramer, salvianolic acid B (SalB), through activation of signal transducer and activator of transcription 3 (STAT3), so that emphysema can be reversed as a result of inhibition of induced cell death, stimulation of cell proliferation and migration, and promotion of stem cell recruitment to the lungs.

SalB was first shown to be potently …

An Evaluation Of Endocrine Disrupting Effects Of Emerging Contaminants Using Daphnia Pulex And Danio Rerio, Lakshmi Neha Reddy Alla

Wayne State University Theses

The limit of the availability of water is based on two factors, scarcity and quality. Conserving and protecting our water resources one of the most critical issues facing humanity as we struggle to deal with contaminated lakes and rivers and climate change. The main aim of this study is to examine toxicity of known water contaminants on aquatic model organisms and be able to develop methodology that will enable the characterization of endocrine disrupting potential of water samples with unknown contaminants. Both the category of water contaminants known as pharmaceuticals, personal care products that are known as PPCPs and other …

Redox Responsive Cerium Oxide Nanoparticles And Cd44 Targeted Nanomicelles For Selective Cancer Therapy, Zhaoxian Wang

Wayne State University Theses

Redox-responsive cerium oxide nanoparticles (CNPs) can play a versatile role in cancer therapy due to their ability to induce oxidative stress under proper pH conditions. Hyaluronic acid micelles with a high affinity to CD44 receptor which achieved more cytotoxicity towards cancer cells. The polymer-coated CNPs and HA-SMA-TPGS-CDF nanomicelles were developed for cancer therapy. The results showed that the toxicity of CNPs in tumor cells was mediated by the pro-oxidant property of CNPs under relative low pH conditions (pH~6.5) of the tumor microenvironment whereas CNPs play a (cytoprotective) anti-oxidant role, scavenging reactive oxygen species and reducing oxidative stress under normal pH …

Endocrine-Disrupting Properties Of Pharmaceuticals And Personal Care Products (Ppcps): An Evaluation Using Aquatic Model Organisms, Manahil Monshi

Wayne State University Theses

Thousands of chemicals have introduced into the environment as a result of human activity since the industrial revolution, and the U.S. Government Accountability Office has estimated that as many as 1,500 new chemical entities are synthesized each year ("Key Issues: Toxic Chemicals - High Risk Issue," 2017). Many of these chemicals are now found in surface water and ground water and can have detrimental effects on environmental health and on human health. This anthropogenic contamination has resulted in the labeling of the diverse array of chemicals found in water, which are not routinely monitored or regulated, as contaminants of emerging …

The Role Of Line-1 Transposable Element In Methamphetamine Neurotoxicity In The Neurogenic Zones, Dongyue Yu

Wayne State University Theses

Methamphetamine (METH) is a widely abused psychostimulant, which can cause neurotoxicity in the striatum and hippocampus. Several epigenetic changes were identified after binge METH exposure, including histone modification, DNA methylation, and changes in miRNA levels. We have shown that binge METH increases expression and activity of Long INterspersed Element (LINE-1), a transposable element, in doublecortin-positive neurons within rat neurogenic zones [1]. The goal of the present study was to identify which type(s) of cells show increases in LINE-1 following binge METH exposure, and determine whether binge METH-induced increases in LINE-1 are associated with cell death. To achieve this goal, male …

Characterization Of The Effect Of Aeration On A Commercially Available Fibrin Sealant For Use In Wound Therapy, Adam Robert Marek

Dissertations

Wound care affects millions of people worldwide each year, and the need for an effective wound therapy still exists. The aim of this study was to characterize a novel, aerated biopolymer, fibrin foam, which is generated through a patented mixing process using a commercially-available fibrin sealant. This research developed a distinct preparation of fibrin foam that creates a porous environment with improved wound healing properties. With this fibrin foam, characterization assessments were performed, including evaluation of mixing parameters, biocompatibility, and biomechanical strengths.

Fibrin foam is created by performing six passes through a mixing device, which generates a foam matrix with …

Axonal Transport, Parkin, And Α-Synuclein; Novel Therapeutic Targets To Treat Methamphetamine Neurotoxicity, Bryan Andrew Killinger

Wayne State University Dissertations

Methamphetamine (METH) is a commonly abuse psychostimulant. Exposure to chronic high doses of METH can result in neurotoxicity primarily characterized by damage to striatal dopaminergic (DAergic) axons. There are currently no therapeutic interventions for METH neurotoxicity. To some extent damage to striatal DAergic axons is reversible and DAergic axon function may return following abstinence from METH. The reversible nature of METH neurotoxicity suggests that normal striatal function could be restored following exposure to METH. However, potential targets to treat METH neurotoxicity are needed. Axonal transport is required for restoration of DAergic axon components damaged or lost following METH. Here we …

Underlying Mechanisms Of Arsenic-Induced Tumorigenesis: From Epigenetics To Malignancy, Lingzhi Li

Wayne State University Dissertations

Arsenic is a well-recognized environmental health threat with the capability of inducing a number of human diseases, including cancer. The aim of this dissertation is to unveil the mechanisms underlying the carcinogenic activities of environmental arsenic. The biological functions of arsenic had been studied for decades. However, there are still many questions that remain to be fully answered, such as whether and how arsenic contributes to the epigenetic regulations and migration or metastasis control of the cancer cells. In this regard, we focused our attention on both histone modifications and miRNA regulations in the arsenic-induced malignant transformation of the cells, …

Human Kinome In Skeletal Muscle Insulin Resistance, Yue Qi

Wayne State University Dissertations

Protein kinases play fundamental roles in regulation of biological processes and functions, such as insulin signaling and glucose metabolism. Dysregulation of protein kinases may cause impaired cell signaling and human diseases, such as metabolic syndrome and type 2 diabetes (T2D). Skeletal muscle is the main site responsible for insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is one of the key features of the pathogenesis of T2D. Therefore, malfunction of protein kinases and their interaction proteins may contribute to the molecular mechanism of insulin resistance in human skeletal muscle. However, no large scale profiling study has been reported to …

Folate Receptor Alpha Targeted Delivery And Characterization Of Polyethyleneimine-Graft-Polycaprolactone-Block-Poly(Ethylene Glycol) Containing Sirna Micelleplexes, Steven Jones

Wayne State University Dissertations

This dissertation focuses on the ability of polyethyleneimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) folate decorated tri-block copolymers ability to deliver a targeted dose of siRNA. The micelleplexes that are formed upon electrostatic interaction with siRNA are used to deliver siRNA in a targeted manner to ovarian cancer cells that over-express Folate Receptor-α (FRα). Each conjugate showed suitable sizes below 200 nm with full siRNA condensation ability. Furthermore, flow cytometry and western blot analysis demonstrated that the best FRα targeted polymer was able to effectively deliver siRNA which resulted in protein knockdown of Toll-like receptor 4 (TLR4). Consequently, TLR4 knock down within SKOV-3 cells …

Three Dimensional Homology Modeling Of Organic Cation Transporter 3 To Identify Structural Elements Mediating Transporter-Substrate Interactions, Hebing Liu

Theses and Dissertations

Organic cation transporters (OCTs) play a pivotal role in the absorption, tissue distribution, and excretion of a diverse array of substances, and currently the nature of the biochemical interactions between substrate and OCTs are unknown. Therefore, identifying which amino acid residues are critical for OCT-substrate interactions is of central importance to understanding and predicting interactions between drugs and OCTs. A three-dimensional (3-D) homology model of human OCT3 was generated using the crystal structure of a high affinity phosphate transporter from Piriformospora indica (PiPT) as template, and putative binding pocket for the prototypical hOCT3 ligand 1-methyl-4-phenylpyridinium (MPP⁺) was identified …

Transferrin Receptor Targeted Delivery Of Sirna For Gene Therapy, Yuran Xie

Wayne State University Dissertations

Gene therapy is thought to be a solution for various difficult to treat diseases such as cancer. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence disease related gene have been exploit in different diseases. However, lack of safe and efficient siRNA delivery systems limits the application of siRNA therapy in clinic. Transferrin receptor (TfR) is an essential transmembrane receptor involved in iron uptake. TfR universally express in most cells/ tissues but upregulated in certain cells, for example, many cancer cells and activated T cells (ATCs). To overcome the biological barriers and increase siRNA delivery efficiency, in …

Protein Phosphatase 2a Interactions In Islet And Human Skeletal Muscle In Diabetes, Divyasri Damacharla

Wayne State University Dissertations

Type 2 Diabetes is a metabolic disorder associated with insulin resistance and consequent high blood glucose levels. Under normal conditions, in response to high blood glucose levels, pancreatic beta cells produce insulin. The secreted insulin is dis-tributed to tissues thereby stimulating insulin stimulated glucose uptake. However, maximum glucose disposal takes place in skeletal muscle. Thus, studying beta cells and skeletal muscle in respect to diabetes is crucial. Protein Phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases belonging to PhosphoProteinPhospha-tase (PPP) family. It constitutes about 80% of all serine/threonine phosphatases. It is regulated by numerous regulatory subunits as well …

Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea, Cristian G. Bologa, Subramani Mani, Oleg Ursu

Biomedical Sciences ETDs

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process.

The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this …

Implementation Of Universal Hplc Analysis For Counterfeit Medication: A Partnership Of Purdue University And The Kilimanjaro School Of Pharmacy, Jordyn Mccord, Michael Mavity, David Wintczak

Purdue Journal of Service-Learning and International Engagement

Jordyn McCord and Michael Mavity are 2016 graduates of both biological engineering and pharmaceutical sciences. David Wintczak is a third-year pharmacy doctoral candidate. Here, in their second article published in PJSL, they describe a weeklong study abroad course at the Kilimanjaro School of Pharmacy in Tanzania, designed to engage students in the implementation of methods for detecting counterfeit medications.

Synthetic And Biological Exploration Of (+)-Boldine - Identification Of Potential Cns Receptor Ligands, Sujay Joseph

Theses and Dissertations

(+)-Boldine, an aporphine alkaloid, is reported to be biologically active at various Central Nervous System(CNS) receptors. However, only a few Structure Activity Relationship(SAR) studies have been conducted using boldine’s aporphine scaffold. A library of novel analogs was synthesized from boldine to understand the effect of bisbenzylation at C2 and C9 positions on the affinity and selectivity at the serotonin receptors.

Spectroscopic Studies Of Anthracyclines: Structural Characterization And In Vitro Tracking, Zeineb Farhane, Hugh Byrne, Malgorzata Baranska

Articles

A broad spectroscopic characterization, using ultraviolet-visible (UV-vis) and Fourier transform infrared absorption as well as Raman scattering, of two commonly used anthracyclines antibiotics (DOX) daunorubicin (DNR), their epimers (EDOX, EDNR) and ten selected analogs is presented. The paper serves as a comprehensive spectral library of UV-vis, IR and Raman spectra of anthracyclines in the solid state and in solution. The particular advantage of Raman spectroscopy for the measurement and analysis of individual antibiotics is demonstrated. Raman spectroscopy can be used to monitor the in vitro uptake and distribution of the drug in cells, using both 488 nm and 785 nm …

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Impacts From The Use Of Antibiotics In Livestock: Methods Of Transmission Of Antibiotic Resistance From Livestock To Humans, Kristin M. Walden

Biology: Student Scholarship & Creative Works

Antibiotic use in livestock production has been around since the 1950s. Antibiotic feed is used in livestock and other meat producing animals for three reasons: illness prevention, illness treatment, and growth promotion. Unfortunately, since the time that antibiotics were first invented, antibiotic resistant bacteria have become a threat to public health. There are many studies showing methods of transmission of antibiotic resistance from livestock to humans. Antibiotic resistance can spread from livestock to soil, water, insects, and food, which ultimately comes into contact with humans. A proposed study to measure antibiotic resistance when eliminating antibiotic feed will provide a hypothesis …

Exploring The Effect Of Novel Small Molecules On Oligodendrocyte Precursor Proliferation, Sagune Sakya

University Scholar Projects

Gliomas, a type of brain tumor, can be difficult to treat and have a poor survival rate. One pathway that leads to glioma formation is excessive signaling by platelet derived growth factors (PDGF) through PDGF receptor α (PDGFRα). Through this research, I found that novel compounds that downregulate PDGFRα decrease proliferation of Oli-neu cells, an oligodendrocyte precursor cell model, and identified signaling pathways through which these compounds may exert their effect. Further investigation may identify targets for development of glioma treatments.

Stabilization Of Gp120 Outer Domain For Hiv-1-1 Vaccine Immunogen Design, Duoyi Hu

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

The sole envelope glycoprotein spike on the surface of Human Immunodeficiency Virus (HIV-1) is composed of two subunits: gp120 and gp41. The gp120 consists of three domains: the inner domain, outer domain and bridging sheet, to which the viral primary receptor CD4 binds and induces a conformational change in gp120 to expose the co-receptor binding site. Previous studies have found that the outer domain of gp120 is relatively more stable than the inner domain and bridging sheet. When superimposed, the co-crystal structures of CD4-gp120 complex and VRC01-gp120 complex revealed that the CD4-binding site (CD4-BS) antibody VRC01 actually mainly bound to …

Investigation Of The Tailoring Steps In Pradimicin Biosynthesis, Kandy L. Napan

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

This research focused on the investigation of the late steps in the biosynthetic pathway of the novel antifungal and antiviral pradimicins A-C. Pradimicins were first isolated from the soil bacterium Actinomadura hibisca. These bioactive molecules are assembled by a type II polyketide biosynthetic pathway. Although the biosynthetic gene cluster of pradimicin has been identified, the functions of the biosynthetic genes and how they work collaboratively to form the final structures of pradimicins remain unknown. This research aims to functionally characterize the enzymes involved in the late steps of the biosynthetic route.

The early biosynthetic steps of pradimicins have been …