Medicinal Chemistry and Pharmaceutics Commons^™

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

UROP Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results of …

Site-Directed Mutagenesis Of Conserved Amino Acids Residues In N5-Carboxyaminoimidazole Ribonucleotide Mutase: Converting N5-Cair Mutase Into Aminoimidazole Ribonnucleotide Carboxylase & Developing A High-Throughput Screening Assay For The Discovery Of N5-Carboxyaminoimidazole Ribonucleotide Mutase, Zhiwen Shi

Wayne State University Theses

The de novo purine biosynthesis pathway plays a critical role in providing new purines to the cell. Previous studies have shown differences between the human and bacterial pathways which suggests that pathway may be a potential target for antibiotic drug discovery. Three critical enzymes are involved in the pathway divergence. In the bacterial pathway, N5-CAIR synthetase (PurK) first converts AIR to N5-CAIR, which is then transformed into CAIR catalyzed by the enzyme N5-CAIR mutase (Class I PurE). In the human pathway, AIR carboxylase (Class II PurE) catalyzes the direct conversion of AIR to CAIR. Class I and Class II PurEs …

Design Of Functional Dendrimer Nanocarriers And Their Formulations In Propellant-Based Inhalers For Pulmonary Drug Delivery, Lin Yang

Wayne State University Dissertations

This Dissertation focuses on addressing two of the major challenges in developing pressurized metered dose inhalers for pulmonary drug / gene delivery to and through the lungs. First challenge is to design biocompatible moieties for the steric stabilization of suspension formulations in HFO-based propellants. Using a combination of tools including ab initio calculation, molecular dynamics simulation and high pressure tensiometry, potential fluorocarbon-philic moieties were systematically screened. Surfactants with those chemistries as tail fragments were studied at the HFO|H2O interface for their ability to lower the interfacial tension at HFO|H2O interface. Selected surfactants were further optimized for surfactant balance by altering …

Species - Dependent Cardiac And Motor Responses To Cholinergic Stimulation In Daphnia Pulex And Daphnia Magna, Bryan James Hannan

Wayne State University Theses

The role of acetylcholine (ACh) in regulating the activity of the heart and `feeding current' driven by the beating thoracic appendages of Daphnia pulex and Daphnia magna was evaluated using acetylcholinesterase inhibitors (AChE-I) and muscarinic receptor agonists. Single animals, tethered to a stainless steel pin, were tested in a watertight aquatic chamber that allowed free movement of appendages and swimming antennae. Heart contraction rate and the rate of thoracic appendage beating were quantified optically by measuring fluctuating changes in light-intensity caused by movement. Physostigmine, neostigmine, oxotremorine, pilocarpine as well as nicotine were used to study ACh and AChE. Atropine was …

Development And Evaluation Of Plga-S-S-Peg Micelles Coencapsulating Curcumin Difluorinated And Paclitaxel For Synergistic Therapeutic Efficacy, Lakshmi Deepika Cheemalakonda

Wayne State University Theses

ABSTRACT

DEVELOPMENT AND EVALUATION OF PLGA-S-S-PEG MICELLES COENCAPSULATING CURCUMIN DIFLUORINATED AND PACLITAXEL FOR SYNERGISTIC THERAPEUTIC EFFICACY

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LAKSHMI DEEPIKA CHEEMALAKONDA

August 2014

Advisor: Dr. Joshua Reineke Major: Pharmaceutical Sciences Degree: Master of Science

Solid tumors like pancreatic tumor has unique property of forming a dense desmoplastic layer around the tumor cells making it difficult for the drug to transport across this layer. Multi drug resistance is also one of the major limitation of chemotherapy. Therefore the aim of this project was to make PLGA-SS-PEG micelles encapsulating CDF and paclitaxel for synergistic cancer therapy. CDF was found to have 16-fold better …

Functional Studies Of 5-Carboxyaminoimidazole Ribonucleotide Synthetase And Mutase From Thermotoga Maritima, Mingyang Zhao

Wayne State University Theses

De novo purine biosynthesis is divergent depending upon the organism. In bacteria, yeasts and plants, 5-aminoimidazole ribonucleotide (AIR) is converted to 4-carboxyaminoimidazole ribonucleotide (CAIR) by N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) synthetase (PurK) and N5-CAIR mutase (Class I PurE). In animals, AIR is converted into CAIR by AIR carboxylase (Class II PurE). The distinction makes PurK and Class I PurE good targets in design of antimicrobial drugs. N5-CAIR is chemically unstable with t1/2 of about 0.9 minutes at pH 7.8 and 37 °C. If the production of N5-CAIR is not regulated relative to its conversion to CAIR, ATP utilization can rapidly become non-stoichiometric. …

Proteomic Discovery Of Protein Phosphatase 1 Catalytic Subunit Protein Interaction Partners In Human Skeletal Muscle, Zhao Yang

Wayne State University Theses

Protein Phosphatase 1 (PP1), a member of Serine/ Threonine Phosphatase family, targets its dephosphorylation activity on serine and threonine residues. As the catalytic subunit of PP1, PP1c can achieve its substrate specificity only by binding with PP1 regulatory subunits. Previous researches have shown that PP1c can involve in multiple functional regulation by associating with various interaction partners. Since serine/ threonine phosphorylation on the Insulin receptor substrate-1 (IRS1) may direct inactivation and degradation of IRS1, this phosphorylation activity is believed to be a source of Insulin Resistance. PP1 is hypothesized to dephosphorylate serine/ threonine site on IRS1, which may rescue the …

Comparative Study Of The Prevalence Of Psk41 In Heterogenous Vancomycin-Intermediate Staphylococcus Aureus Isolates Against Non- Heterogenous Vancomycin-Intermediate Staphylococcus Aureus Isolates And The Prevalence By Patient Severity, Poorva Mukund Divekar

Wayne State University Theses

COMPARATIVE STUDY OF THE PREVALENCE OF PSK41 IN HETEROGENOUS VANCOMYCIN-INTERMEDIATE STAPHYLOCOCCUS AUREUS ISOLATES AGAINST NON- HETEROGENOUS VANCOMYCIN-INTERMEDIATE STAPHYLOCOCCUS AUREUS ISOLATES AND THE PREVALENCE BY PATIENT SEVERITY

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POORVA DIVEKAR

December 2014

Advisor: Dr. Emily T. Martin

Major: Pharmaceutical Sciences

Degree: Master of Science

Earlier studies have reported that pSK41 plays an important role in the transfer of vancomycin resistance from Vancomycin-resistant Enterococci (VRE) to S. aureus. This transfer leads to the development of Vancomycin-resistant S. aureus (VRSA). Thirteen VRSA cases have been reported in the United States since 2002. To determine and compare the prevalence of pSK41 in hVISA isolates …

Synthesis And Characterization Of Brain Penetrant Prodrug Of Neuroprotective D264: Potential Disease Modifying Treatment Agent For Parkinson's Disease, Fahd Shamoon Dholkawala

Wayne State University Theses

Parkinson's disease (PD) is a complex neurodegenerative disorder with progressive loss of dopamanergic neurons in the substantia nigra region of the brain and accumulation of intracytoplasmic inclusions called `Lewy bodies'. PD is characterized by tremors, rigidity, slowness of movement, bradykinesia and postural imbalances. Although the etiology of PD is not well understood, it is well established that oxidative stress, mitochondrial dysfunction, alpha-synuclein aggregation play a central role in the pathogenesis of PD. Current treatment methods are based on symptomatic relief without addressing the underlying pathophysiological factors responsible for the disease. It is important to develop therapies which can address these …

Multi-Component Microparticulate/Nanoparticulate Dry Powder Inhalation Aerosols For Targeted Pulmonary Delivery, Xiaojian Li

Theses and Dissertations--Pharmacy

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution.

The physicochemical properties of multi-component dry …

Phosphatidylinositol 3-Kinase (Pi3k) As A Therapeutic Target In Nsclc, Christopher W. Stamatkin

Theses and Dissertations--Pharmacy

Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using …

Β-Lactam Estrogen Receptor Antagonists And A Dual-Targeting Estrogen Receptor/Tubulin Ligand, Niamh O'Boyle, Jade K. Pollock, Miriam Carr, Andrew Js Knox, Seema M. Nathwani, Shu Wang, Laura Caboni, Daniela M. Zisterer, Mary Meegan

Articles

Twelve novel β-lactams were synthesised and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC₅₀ values: 40 and 8 nM respectively) and ERβ (IC₅₀ values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G₂/M phase (mitotic blockade) and depolymerisation of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation …

Dual Delivery Systems Based On Polyamine Analog Benspm As Prodrug And Gene Delivery Vectors, Yu Zhu

Wayne State University Dissertations

Combination drug and gene therapy shows promise in cancer treatment. However, the success of such strategy requires careful selection of the therapeutic agents, as well as development of efficient delivery vectors. BENSpm (N1, N11-bisethylnorspermine), a polyamine analogue targeting the intracellular polyamine pathway, draws our special attention because of the following reasons: (1) polyamine pathway is frequently dysregulated in cancer; (2) BENSpm exhibits multiple functions to interfere with the polyamine pathway, such as to up-regulate polyamine metabolism enzymes and down-regulate polyamine biosynthesis enzymes. Therefore BENSpm depletes all natural polyamines and leads to apoptosis and cell growth inhibition in a wide range …

Novel Compounds As Potential Alzheimer's Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome, Jeremy E. Chojnacki

Theses and Dissertations

Alzheimer’s disease is a devastating neurodegenerative disorder and the leading cause of dementia. The disease manifests via several pathologies including neuroinflammation, oxidative stress, metal ion dyshomeostasis, and cell death. To address the multifaceted nature of this disorder, the design of several diverse compounds, targeting many pathological effects, was generated. First, a series of compounds based on curcumin and diosgenin were synthesized following the bivalent design strategy. Two compounds were discovered to have neuroprotective ability, anti-oxidative function, and anti-Aß oligomerization (AßO) properties. A second set of molecules was also designed, wherein a hybrid compound strategy was utilized. Three hybrids were to …

Studies On Two Polyherbal Formulations (Zpto And Zto) For Comparison Of Their Antidyslipidemic, Antihypertensive And Endothelial Modulating Activities, Nauman Aziz, Malik Hassan Mehmood, Anwarul Hassan Gilani

Department of Biological & Biomedical Sciences

Background

Cardiovascular disorders (CVDs) are the leading cause of disease burden worldwide. Apart from available synthetic drugs used in CVDs, there are many herbal formulations including POL-10 (containing 10 herbs), which have been shown to be effective in animal studies but POL-10 was found to cause tachycardia in rodents as its side effect. This study was designed to modify the composition of POL-10 for better efficacy and/or safety profile in CVDs.

Methods

To assess the antidyslipidemic, antihypertensive and endothelial modulatory properties of two herbal formulations, (ZPTO and ZTO) containing Z: Zingiber officinalis, P: Piper nigrum, T: Terminalia belerica and …

Investigation Of The Structure And Dynamics Of Regioisomeric Eu³⁺ And Gd³⁺ Chelates Of Nb-Dotma: Implications For Mri Contrast Agent Design, Benjamin Charles Webber

Dissertations and Theses

The detection of disease and abnormal pathology by magnetic resonance imaging (MRI) has been aided significantly by the use of gadolinium (Gd³⁺)-based contrast agents (CAs) over the past three decades. MRI and MRI CAs play a critical role in diagnosing tumors and diseases of the central nervous system. The agents used clinically have been shown to safely increase MRI contrast despite the toxicity of Gd³⁺, owing to the high kinetic and thermodynamic stability of these chelates. However, current CAs enhance contrast at a small fraction of what is theoretically possible. This leads to the necessity of …

Cytochrome P450 Family 1 Inhibitors And Structure-Activity Relationships, Jiawang Liu, Jayalakshmi Sridhar, Maryam Foroozesh

Faculty and Staff Publications

With the widespread use of O-alkoxyresorufin dealkylation assays since the 1990s, thousands of inhibitors of cytochrome P450 family 1 enzymes (P450s 1A1, 1A2, and 1B1) have been identified and studied. Generally, planar polycyclic molecules such as polycyclic aromatic hydrocarbons, stilbenoids, and flavonoids are considered to potentially be effective inhibitors of these enzymes, however, the details of the structure-activity relationships and selectivity of these inhibitors are still ambiguous. In this review, we thoroughly discuss the selectivity of many representative P450 family 1 inhibitors reported in the past 20 years through a meta-analysis.

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

Dissertations and Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with ^99mTc and ⁶⁸Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both ^99mTc-N4amG and ^99mTc-GP were stable up to 6 hours, whereas ⁶⁸Ga-GP was stable up to 2 hours. Cell culture studies …

Mechanisms Of Cytokine-Induced Metabolic Dysfunction Of The Pancreatic Beta-Cell, Abiy Mussa Mohammed

Wayne State University Dissertations

MECHANISMS OF CYTOKINE-INDUCED METABOLIC DYSFUNCTION OF THE PANCREATIC BETA-CELL

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ABIY MUSSA MOHAMMED

August 2013

Advisor: Dr. Anjaneyulu Kowluru

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Type I diabetes is characterized by an absolute insulin deficiency due to loss of pancreatic â-cell mass by autoimmune aggression. During the progression of the disease proinflammatory cytokines such as IL-1â, TNFá and INFã are secreted by infiltrated and activated T-cells and macrophages which ultimately damage the pancreatic â-cell. However, the signaling mechanisms involved in cytokine-induced damage are only partially understood. Phagocyte-like NADPH oxidase [NOX2] has been shown to play regulatory roles in the …

Polymeric Nanocarriers And Their Oral Inhalation Formulations For The Regional Delivery Of Nucleic Acids To The Lungs, Denise Santos Conti

Wayne State University Dissertations

Gene therapy has attracted attention in the fields of medicine, pharmacy, and bionanotechnology due to the potential for treating a large number of medically relevant diseases. Oral inhalation (OI) is a promising route for the administration of therapeutics, including small molecules and biomacromolecules, such as nucleotides, peptides, and proteins, to (locally) and through (systemically) the lungs. The use of OI is especially attractive for the delivery of nucleic acids as it provides a direct and non-invasive route for targeting the lungs. Pressurized metered-dose inhalers (pMDIs), are the most commonly used OI in treatment of lung diseases and are thus promising …