Pharmacy and Pharmaceutical Sciences Commons^™

Computer-Aided Drug Design Of Bakuchiol-Inspired Lxrα Modulators Against Acute Lymphoblastic Leukemia, Dillon P. Cao

LSU Master's Theses

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of pediatric malignancies. Although glucocorticoids are commonly used to treat ALL, prolonged use can lead to steroid resistance, rendering the drug regimen ineffective. Therefore, alternative treatment avenues are needed for high- risk pediatric patients that do not respond well to traditional regimens.

Liver X Receptor α (LXRα) is presented as a potential alternative drug target for pediatric patients that exhibit suboptimal response to glucocorticoids. Limitations of the current LXRα modulators such as indiscriminate isoform selectivity between LXRα and LXRβ and consequent adverse effects …

Cultivating Health, Not Wealth In The United States' Healthcare System: Comprehensive Revisions For The Orphan Drug Act Of 1983, Kayla Smith

Regis University Student Publications (comprehensive collection)

This thesis explores the way in which the Orphan Drug Act of 1983, originally instituted in response to a lack of treatments for rare diseases in the United States of America, has failed to achieve its initial objectives in the 40 years since its implementation. In evaluating various successful examples of government subsidization programs designed to intervene in private industry, this thesis composes the criterion required for funding-based legislation which maximize market outcomes while minimizing tax-payer burden. An analysis of the synthetic organic chemistry industry – and a case study into the production of a particular orphan treatment for a …

Design And Synthesis Of Non-Xanthone Structural Analogs Of Α-Mangostin, Maryam Foroozmehr

Theses and Dissertations

α-Mangostin belongs to a class of polyphenolic compounds called xanthones. The potential pharmacological effects such as anti-bacterial and anti-cancer effects of α-mangostin have made it an important natural product for medicinal chemistry evaluation. During this thesis research, we have designed and synthesized a series of non-xanthone analogs of α-mangostin for medicinal chemistry evaluation. A commercially available starting material, methyl-4-methoxysalicylate was used to synthesize these non-xanthone analogs. The analogs were designed as more flexible derivatives compared to the tricyclic motif within α-mangostin yet retain the hydroxybenzoate scaffold. Through a one-pot chemical synthesis, with relatively high yield (70%), we prepared eight different …

Carborane-Appended Levodopa For Prostate-Specific Membrane Antigen And Boron Neutron Capture Therapy, Alejandra Macias

Graduate Research Theses & Dissertations

A multi-step organic synthetic method to attach carborane cages to biocompatible organic compounds for application in Boron Neutron Capture Therapy (BNCT) was conducted. Boron Neutron Capture Therapy is a form of radiation therapy that promises a new and effective form of cancer treatment that involves the destruction of tumor cells using an isotope of boron (10B). The effectiveness of this therapy depends on the boron content accumulated in cancerous tissue. Carboranes are boron-rich clusters that possess unique physical and chemical properties making them suitable for a wide range of applications including medicinal chemistry. Because of their high boron content, carborane-appended …

Synthesis Of Fluorinated Pyrazoles Via Intra- And Intermolecular Cyclization Reactions, Matthew Saucier

Honors Theses

Pyrazole-based pharmaceuticals treat a wide array of diseases and conditions including obesity, diabetes, cancer, microbial and viral infections, pain and inflammation, and many neurological disorders. Syntheses for this biologically significant substrate have been well developed, but current methods to afford fluorinated pyrazoles are limited by variability and selectivity. By 2013, over 25% of all drugs available on the market contained the element fluorine due to its unique characteristics leading to improved target protein binding, bioavailability, and metabolic stability. In order to harness these pharmaceutical benefits of fluorine and overcome its difficulty in handling and stability, we set out to develop …

Studies On The Size And Non-Planarity Of Aromatic Stacking Moiety On Conformation Selectivity And Thermal Stabilization Of G-Quadruplexes, Mandeep Singh

University of the Pacific Theses and Dissertations

Targeting DNA has the advantage over proteins for cancer remediation because of the fewer copies of the ligands required for the desired therapeutic effect. Traditionally, covalent DNA binders like alkylating agents have been used to induce genetic instability through the formation of DNA lesions and strand breaks, leading to cellular apoptosis. The primary drawback of this treatment is the non-specific binding that affects both cancerous and non-cancerous cells. G-quadruplexes are the DNA secondary structures that are present in abundance near the promoter regions of the oncogenes and are involved in the regulation of their activities. A ligand-mediated stabilization of G-quadruplexes …

Structure Elucidation Of A Pyrrolobenzodiazepine Alkaloid And A Biologically Active Polyketide Produced By Rhodococcus Sp. Mtm3w5.2 Via Two-Dimensional Nmr Spectroscopy, Garrett Johnson

Electronic Theses and Dissertations

As the battle against ever-increasing drug resistence bacteria rages on, novel and sometimes more complex natural products can be used to combat this. In this study, two-dimensional NMR techniques were utilized to collect a complete spectral data set for two natural products. The first structure, a synthesized Pyrrolobenzodiazepine alkaloid natural product was confirmed through these methods. The second, a strain of Rhodococcus, MTM3W5.2, produces a novel antibacterial molecule in broth cultures and the active compound was fractionated using a Sephedex LH-20 column. Chromatographic purification yielded a pure sample at 58.90 minutes, RT.58. HRMS data deduced an exact mass of …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Extraction And Purification Of (E)-Resveratrol From The Bark Of Maine's Native Spruces, Panduka S. Piyaratne

Electronic Theses and Dissertations

Resveratrol is a plant secondary metabolite which protects plants from pathogenic invasions and acts as a remedial agent against injury, stress, and tissue damage by UV radiation. With its characteristic stilbene structure, resveratrol adopts (E) and (Z) isomeric forms. However, the (E) isomer is the most biologically active and abundant form of resveratrol in nature.

(E)- Resveratrol confers a variety of benefits to human health and well-being. Besides its antioxidant activity, the role of (E)-resveratrol as an anti-inflammatory, anti-aging, cardioprotection, and anticancer agent has been a widely explored research interest. …

Synthesis And Evaluation Of Tetrahydroprotoberberines As Dopamine Receptor Ligands, Satishkumar V. Gadhiya

Dissertations, Theses, and Capstone Projects

Dopamine (DA) receptors belong to the G-protein coupled receptors (GPCRs) family, divided in to two groups based on their high homology transmembrane domains; D1-like DA receptors (D1, D5) and D2-like DA receptors (D2-D4). DA receptor specific ligands have been exploited as a means for studying the prognosis and curing several CNS disorders. Though several efforts have been devoted to discover selective and potent DA receptor ligands, complete selectivity within the DA receptor subtypes remains a challenge.

Tetrahydroprotoberberines (THPBs) are a group of naturally occurring tetracyclic alkaloids that belong to the tetrahydroisoquinoline family. A wide range of biological activities are associated …

Discovering Small Molecule Inhibitors Targeted To Ligand-Stimulated Rage-Diaph1 Signaling Transduction, Jinhong Pan

Legacy Theses & Dissertations (2009 - 2024)

The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of …

A Diversity-Oriented Synthesis Approach To Functionalized Azaheterocycles Using Cyclic Alpha-Halo Eneformamides, Spencer A. Langevin

All Master's Theses

Functionalized piperidines, azepanes, azamacrocycles, morpholines, and thiomorpholines are common structural motifs found in a wide range of pharmaceuticals such as carmegliptine, levofloxacin, thioridazine, claviciptic acid, and azithomycin. As a result, there is a strong desire to construct highly functionalized nitrogen-bearing ring scaffolds in order to construct a wide range of drug possibilities. There are several non-modular and step-uneconomical synthetic methods used in the construction of these aforementioned motifs such as ring closing metathesis, ring expansions, and intramolecular reductive amination. In this research, we present a step-economical, cost-effective, scalable, and diversity-oriented synthesis approach to highly functionalized N-heterocycles through the intermediacy of …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Synthesis Of Medicinally Relevant Thiazolyl Aryl Ketones Under Mild Conditions, Danielle M. Gardner

Health, Human Performance and Recreation Undergraduate Honors Theses

Purpose: The growing amount of clinical resistance observed in current antifungal drugs and in anti-HIV pharmaceuticals is a concern in the medical community. The purpose of this study is to develop a mild synthetic process for biomedically relevant thiazolyl aryl ketones that can be used to develop antifungal and anti-HIV drugs. We hypothesized that the proposed synthetic technique would be more efficient, produce fewer unwanted byproducts, and be more tolerant of functional groups than existing methods.

Methods: Prior to each of the ketone reactions, the necessary salt was synthesized by mixing thiazole and 9-bromofluorene neat in a reaction tube heated …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Design, Synthesis, And Pharmacological Evaluation Of Three Series Of Lobelane Analogs As Inhibitors Of The Vesicular Monoamine Transporter (Vmat2), John P. Culver

Theses and Dissertations--Pharmacy

Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane …

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres

Doctoral Dissertations

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …

Design, Synthesis And Biological Evaluation Of Novel Compounds With Cns-Activity Targeting Cannabinoid And Biogenic Amine Receptors, Alexander M. Sherwood

University of New Orleans Theses and Dissertations

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function.

The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at …

Synthesis Of Novel Azetidines, Amber Thaxton

University of New Orleans Theses and Dissertations

Azetidine is a four-membered nitrogen-containing heterocyclic ring that has recently received a great deal of attention as a molecular scaffold for the design and preparation of biologically active compounds. Structure-activity studies employing functionalized azetidines have led to the development of variety of drug molecules and clinical candidates encompassing a broad spectrum of biological activities.

Herein, the synthesis a novel series of 3-aryl-3-arylmethoxyazetidines is described. Selected 3-aryl-3-arylmethoxyazetidines were evaluated for their binding affinity to multiple monoaminergic transporters for the potential treatment of methamphetamine addiction. It was discovered that this scaffold exhibits high binding affinity (nM) for both the serotonin and dopamine …

New Applications Of Mass Spectrometry For Drug And Lipid Analysis, Elizabeth Lauren Emerson

Graduate Theses and Dissertations

Mass spectrometry is an important tool used in many different disciplines and settings that include forensics, drug discovery, environmental analysis, and proteomics. Gas chromatography - mass spectrometry (GC-MS) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI - TOF MS) are two of the most important instruments used for analysis of compounds. Chapters 1 and 2 of this discussion use GC-MS for the investigation of synthetic cannabinoids in `K2' incense products and the detection of metabolites in urine samples from individuals suspected of consuming these mixtures. Analytical standards were synthesized and used for identification and confirmation of structures. Detection of …

Library Synthesis Of Anticancer And Antibacterial Agents Via Azide Chemistry, Jianjun Zhang

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Various anticancer and antibacterial agents have been synthesized via azide chemistry by taking advantage of carbohydrate. Starting from the synthesis of 14 glycosyl azides, a library of carbohydrate-oxazolidinone conjugates and a library of carbohydrate-cyclopamine conjugates with biological interests were synthesized based on a highly efficient "click reaction" assisted by sonication. Some of the conjugates have improved solubility and enhanced anticancer activity.

A library of neomycin B derivatives with various modifications at the 5" position has been synthesized. Two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Antibacterial activities were measured when combined with other …

Development Of Novel Ahr Antagonists, Hyosung Lee

University of Kentucky Doctoral Dissertations

Aryl hydrocarbon receptor (AHR) is a sensor protein, activated by aromatic chemical species for transcriptionally regulating xenobiotic metabolizing enzymes. AHR is also known to be involved in a variety of pathogenesis such as cancer, diabetes mellitus, cirrhosis, asthma, etc. The AHR signaling induced by xenobiotics has been intensively studied whereas its physiological role in the absence of xenobiotics is poorly understood. Despite a number of ligands of AHR have been reported thus far, further applications are still hampered by the lack of specificity and/or the partially agonistic activity. Thus, a pure AHR antagonist is needed for deciphering the AHR cryptic …

Synthesis Of Dihydroisoquinolines And Tetrahydroisoquinolines, John J. Schlager

Chemistry & Biochemistry Theses & Dissertations

Dihydroisoquinolines and tetrahydroisoquinolines are compounds which possess a variety of pharmacological activities. New easier methods of synthetic manipulations of these structures is of constant interest in the pharmaceutical industry.

This paper describes a new three step method of preparing 1-alkyl- and 1-aryl-tetrahydroisoquinolines from a tetrahydroisoquinoline. The synthesis involves the N-chlorination of tetrahydroisoquinoline followed by dehydrohalogenation with potassium superoxide. The reaction products are the dihydroisoquinolines. Overall yields range from 85-96%. The unsubstituted, 1-methyl-, and 1-phenyl-J,4-dihydroisoquinolines have been formed. Organometallation of the unsubstituted dihydroisoquinoline provides the 1-substituted tetrahydroisoquinoline. The 1-benzyl-, 1-n-butyl-, 1-ethyl-, 1-methyl-, and 1-phenyl-1,2,J,4-tetrahydroisoquinolines were prepared. The use of Grignard and …