Medicinal-Pharmaceutical Chemistry Commons^™

Catalytic Synthesis Of Protoberberine Alkaloids And Their Evaluation As Selective Dopamine Receptor Ligands, Ashok Reddy Gudipally

Dissertations, Theses, and Capstone Projects

Dopamine regulates motor control, cognition, reward, motivation, and neuroendocrine signaling. Disruption of dopaminergic neurotransmission is closely linked to central nervous system disorders, including Parkinson’s disease, schizophrenia, addiction, and related neuropsychiatric conditions. Because these functions are mediated by multiple dopamine receptor subtypes with distinct roles in physiology and disease, the discovery of subtype-selective ligands remains an important goal in neuropharmacology. Within this context, protoberberine alkaloids, particularly tetrahydroprotoberberines (THPBs), are attractive molecular frameworks because they combine structural complexity with broad biological relevance, including measurable activity in CNS-related diseases. Prior work from our laboratory and others established (–)-stepholidine (1.60) as an important lead …

Multicomponent Reaction-Initiated Synthesis Of Polyheterocyclic Compounds, Ashutosh Nath

Graduate Doctoral Dissertations

Efficient synthesis of novel heterocycles with biological interest remains a challenge in modern organic chemistry. This dissertation presents the development of efficient synthetic strategies that combine multicomponent reactions (MCRs) with sequential reactions for rapid access a diverse array of polyheterocyclic compounds. The projects are: 1) Groebke-Blackburn-Bienaymé (GBB) reaction followed by N-acylation and Friedel-Crafts (FC) cyclization for the construction of imidazopyridine- and indole-fused azepinones involving an unusual ring-expansion process. 2) Modified GBB condensation products for intramolecular Diels-Alder (IMDA) cycloaddition and dehydrative re-aromatization to access imidazopyridine-fused isoquinolinones. 3) Integration of the Ugi-three component reaction (Ugi-3CR) and Pictet-Spengler (PS) reaction followed by …

Development Of Minimalist Trifunctional Building Blocks For Chemical Biology Probe Synthesis, Luke E. Bohrer

Electronic Theses and Dissertations

The completion of the Human Genome Project in 2003 generated expectations that genomic information would accelerate the discovery of new protein drug targets and FDA-approved therapies. However, many small-molecule drug candidates continue to fail in clinical trials, and much of the human proteome remains undercharacterized in terms of structure, function, and disease relevance. Chemical tools are therefore essential for defining protein function, mapping protein interactions, and identifying disease-associated molecular mechanisms. Among these tools, small-molecule chemical probes provide a powerful strategy for connecting biological activity with target identification, functional analysis, and the development of effective therapies.

This dissertation describes the development …

Supramolecular Assembly In Short Peptide Systems For Selective Metabolite Recognition And Drug Nanoencapsulation, Maithreyi Ramakrishnan

Dissertations, Theses, and Capstone Projects

Short peptides can form adaptive supramolecular assemblies, and understanding how minimal sequences organize around neurometabolites or hydrophobic cancer drugs enables the rational design of functional materials. This thesis combines molecular dynamics with experimental validation to establish design rules linking peptide sequence to emergent structure and function. Chapter 1 outlines the molecular determinants governing peptide assembly. Chapter 2 reviews computational workflows that reveal sequence-dependent conformations and supramolecular organization. Chapter 3 applies these principles to Dynamic Peptide Libraries which identify tetrapeptides that selectively interact with neurometabolites. Chapter 4 extends the same interaction-driven framework to design tryptophan-rich pentapeptides that co-assemble with kinase inhibitors …

Computer-Aided Development Of Novel Antioxidants, Rita Bernadett Vlocsko

Graduate Doctoral Dissertations

Physiological redox homeostasis is a fine balance between prooxidants and antioxidants that are integrated elements of several reduction-oxidation mechanisms at molecular, organellar, cellular and tissue levels. When this equilibrium is disrupted and prooxidants become dominant, the body relies on endogenous and exogenous antioxidants to counterbalance the dysregulation and ultimately prevent the progression of oxidative stress. Reactive species (reactive oxygen species, reactive nitrogen species, or reactive sulfur species) are significant contributors to prooxidant activity. Over the years, substantial knowledge has been accumulated regarding their origin and roles in disease development, leading to the discovery and development of antioxidants that effectively target …

Small Molecule Antioxidants As Potential Therapeutics For Preeclampsia, Maxim Mastyugin

Graduate Doctoral Dissertations

The major goal of this work was to develop a therapeutic intervention against preeclampsia (PE). Preeclampsia affects up to 5-7% of all pregnancies and has no causative treatments. It is associated with oxidative stress caused by a prolonged ischemic state and increase in reactive oxygen species (ROS) in the placenta. The cardinal symptoms include high blood pressure, kidney dysfunction, and in severe cases, eclampsia. With no treatment for the underlying causes available, we offer small molecule antioxidants which may scavenge ROS in the placenta arising from the initiating event of PE, the oxidative stress. By reducing placental ROS, these antioxidants …

Membrane Organization Of Rheb And Rhoa: Roles In Function And Allosteric Druggability, Chase M. Hutchins

Dissertations and Theses (Open Access)

Small GTPases of the Ras superfamily are membrane-bound molecular switches that regulate nearly all major cellular processes, and their dysregulation drives cancers, neurological disorders, and metabolic diseases. While anchored to cellular membranes, the catalytic domains of small GTPases undergo orientation dynamics, adopting distinct configurations that can occlude or expose effector-binding surfaces and modulate signaling output. These dynamics have been characterized in the Ras oncoproteins, but whether they extend across the superfamily and influence allosteric druggability has remained unknown.

In this dissertation, I address these questions through Rheb and RhoA, two small GTPases with complementary differences in subfamily lineage, membrane localization, …

Exploring The Limitations Of Substrate Scope In Dimethylallyltryptophan Synthases, Evan T. Miller

Theses and Dissertations--Pharmacy

Natural products (NPs), are the largest source of bioactive compounds in Nature, and are essential to the treatment of human disease. Nearly 50% of drugs approved for use from 1981 to 2019 owe some aspect of their development to NPs, either in terms of their structure, pharmacophore, or mechanism of action. However, NPs are difficult to structurally optimize. Chemoenzymatic methods for NP derivatization have been increasingly seen as practical alternatives to traditional synthetic methods. Prenyltransferases (PTs) are involved in the primary and secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically …

Recent Studies On The Reactions And Synthesis Of Nitrogen And Sulfur - Containing Heterocyclic Pharmacophores., Bernard Louis Adjei

Electronic Theses and Dissertations

Nitrogen and sulfur-containing heterocycles remain significant classes of compounds in the field of medicinal and organic chemistry due to their unique structural features and diverse biological activities which make them of considerable interest for drug discovery and development. Notable examples of the nitrogen containing heterocycles include the phthalimide and glutarimide rings present in thalidomide. Thalidomide, a potent small-molecule therapeutic agent, precipitated a significant global drug crisis due to its teratogenicity, causing congenital malformations in phocomelia infants, which remains unrivaled over half a century ago. Currently, thalidomide derivatives are extensively utilized in the therapeutic management of various hematological malignancies. Recent investigations …

Quantum Chemical Methods And Multiscale Modeling In Computer-Aided Drug Design, Hunter W. La Force

Chemistry Theses and Dissertations

Computer-Aided Drug Design (CADD) leverages a diverse toolkit of computational methods to accelerate the discovery and development of novel therapeutics. Among these, quantum chemical calculations provide unparalleled accuracy in understanding molecular interactions, albeit at a higher computational cost. This accuracy is crucial for identifying and quantifying fundamental interactions that dictate drug efficacy and selectivity, as exemplified by our investigation of ruthenium polypyridyl complexes. These metal-based compounds are model systems for studying covalent coordination bonds between ruthenium and its ligands and noncovalent interactions with DNA and protein targets. Local Mode Vibrational Theory emerges as a powerful lens within this framework, enabling …

Trade-Off Between Limonene & Geraniol-Based Reprocessable And Non-Reprocessable Epoxy Thermosets: Role Of Aliphatic Diamines In Polymer Networks Design, Priyankkumar Kanubhai Patel

Electronic Theses & Dissertations

The growing demand for sustainable materials, driven by environmental concerns and the rapid depletion of fossil fuels, has garnered significant attention in the fabrication of bio-based epoxy thermosets as renewable alternatives to petroleum-derived thermosetting polymers. The present study focuses on the synthesis and characterization of epoxy prepolymer resins derived from limonene and geraniol via a two-step process, followed by the fabrication of thermally cross-linked flexible epoxy thermoset films using various traditional aliphatic diamine curing agents, namely 1,2-ethylenediamine (EDA), 1,4-butylenediamine (BDA), and 1,6-hexamethylenediamine (HDA). Additionally, the incorporation of cystamine, a disulfide-containing diamine, enabled the formation of a covalent adaptable network through …

Antiproliferative Effects Of Salvia On Breast Cancers., Allison C. Portaro

College of Arts & Sciences Senior Theses

Breast cancer is the most common cancer diagnosed in female adults, with 2.3 million new cases worldwide in 2020. Plants have been used in traditional medicine and are a potential source of pharmaceuticals. One example is the large Lamiaceae (mint) family. The Salvia genus, commonly known as the sages, is the largest genus in Lamiaceae with almost 900 known species. Salvia lyrata (lyre-leaved sage) has a history of Native American medicinal use to treat cancers and other ailments resulting in this plant being referred to as ‘cancer weed.’ Extracts were produced from the leaves of S. lyrata, S. lyrata …

Biophysical Studies Of Nucleic Acid - Small Molecule Recognition, Andrea Conner

All Dissertations

The presented work is a collection of studies performed to examine small molecule recognition of nucleic acids. Recognition of nucleic acids was examined using two types of small molecules: aminoglycosides and Hoechst dyes. Chapter One focuses on established experimental techniques (i.e. absorbance, isothermal titration calorimetry, flow cytometry, cell microscopy, etc.) in small molecule recognition of nucleic acids. The emphasis of studies in the group has been on two focus areas. (i) Thermodynamic characterization of mixed A-form and B-form DNA or RNA conformation with aminoglycosides, particularly neomycin-class. (ii) Characterization of new Hoechst-morpholine (HT-MO) derivatives’ interactions with nucleic acids.

Focus area (i) …

The Analysis Of Reference Standard Storage Failures Through The Use Of Ibuprofen, Hope Vonder Brink

Honors Projects

Reference standards are commonly used in drug chemistry. They are used to calibrate the instruments and serve as a known point of reference for analysts’ ability to compare unknowns. Drugs can degrade over time or through environmental factors, causing contaminants to be present. In the event of environmental degradation while in storage, such as the exposure to high heat, it would be beneficial to have a database of known breakdown products in common drug reference standards for analysts’ reference. Using ibuprofen as an exemplar drug, this study attempted to identify the thermal breakdown products of ibuprofen and introduce the proposed …

Solvation Thermodynamic Mapping Approaches For Computer-Aided Drug Discovery, Vjay Molino

Dissertations, Theses, and Capstone Projects

The drug discovery process is inherently long and costly, prompting the development and integration of computational tools to mitigate these challenges. One of area explored in computer-aided drug discovery is to understand the role of solvation in protein-drug binding and to develop computational tools and methods that can be integrated in the drug discovery process. Grid Inhomogeneous Solvation Theory (GIST) is a tool that provides a framework for mapping solvation thermodynamiproperties of water molecules on the protein surface.This thesis explores the use of GIST in generating pharmacophore models and elucidates the role of solvation in protein structural fluctuations.

One of …

The Role Of Confined Hydration And Water Reorganization In Molecular Binding, Joe Z. Wu

Dissertations, Theses, and Capstone Projects

An important factor in guiding the development of drug discovery efforts is the comprehensive assessment of a ligand or drug’s ability to bind its receptor. The metric used to measure this interaction strength is by calculating the binding free energy (BFE). To achieve this accurately, we combine two concepts: (1) Grid Inhomogeneous Solvation Theory (GIST) returns the local water thermodynamic and structural contributions to free energy; and the (2) Alchemical Transfer Method (ATM) obtains the absolute (ABFE) and relative binding free energy (RBFE) estimates between ligand pairs. In this work, we employ Alchemical Water-Transfer to tether bridging water(s) during the …

Asymmetric Synthesis Of The Hiv Protease Inhibitor Tmc-126 And An Anti-Malarial Agent Via A Titanium Tetrachloride Mediated Asymmetric Glycolate Aldol Addition Reaction. Redefining The Curtius Rearrangement Reaction Via Dehomologation Of Carboxylic Acids Bearing Alpha-Leaving Groups, Kweku Amaning Affram

Theses and Dissertations

Acquired Immune Deficiency Syndrome (AIDS) and malaria are two devastating infectious diseases caused by HIV and Plasmodium parasites. AIDS is caused by HIV-1 and HIV-2, transmitted through sexual contact, blood transfusions, needle sharing, and perinatal routes. Malaria, caused by plasmodium parasites through mosquito bites. Today, millions of people around the world have been infected with HIV and malaria and much research has been done to treat it. However, despite advancements in therapeutic options, these diseases remain a significant global health threat, particularly in developing countries due to the emergence of drug-resistant strains for both HIV and malaria complicating eradication efforts. …

The Development Of A One Pot, Two Reaction Synthetic Preparation Of 1,2,4-Oxadiazole, And Synthesis Of Ataluren, A Novel Drug In The Fight Against Duchenne Muscular Dystrophy. Efforts Towards The Synthesis Of A Potential Protease Inhibitor Against The Main Protease (3clpro) Of Covid-19, Austin J. Carter

Theses and Dissertations

1,2,4-Oxadiazoles are five-membered heterocyclic structures first synthesized by Tiemann and Krüger in 1884. Recent discoveries suggest an array of useful biological properties.In preparation of 1,2,4-oxadiazoles, the most prevalent precursors are amidoximes, which can be created via the reaction of nitriles with hydroxylamine hydrochloride and a base. The amidoximes are reacted with an activated carboxylic acid to yield an acylated intermediate. This intermediate can be exposed to a base to cyclize into the 1,2,4-oxadiazole. This thesis describes the efforts in combining these three steps into a unified one-pot synthesis.

Currently, there are a significant number of commercially available FDA approved and …

Alpha-Synuclein Interaction With Gedunin, Tony Matundura Nyabayo

Graduate Theses/Dissertations

Parkinson’s disease (PD) and other Proteinopathies develop when α-synuclein misfolds and aggregates into toxic amyloids. While existing treatments for PD are primarily focused on managing its symptoms, a viable solution for slowing down the progress of Parkinson’s disease involves targeting the toxic α-synuclein amyloids. Gedunin, a natural inhibitor of heat shock protein 90, has been extensively used to treat malaria. Also, recent research investigations have shed light on its potential beyond malaria therapy, indicating that Gedunin may offer a possible solution for treating a variety of neurodegenerative diseases. Using plate-based assays, we examined how Gedunin influences α-synuclein fibrillation and its …

Rwanda's Natural Remedies: A Fresh Look At The Fight Against Malaria, Leandre Nsabimana Ndisanze

Pomona Senior Theses

Malaria remains one of the most devastating parasitic diseases globally, disproportionately affecting sub-Saharan Africa, where Rwanda continues to face high transmission rates and rising resistance to conventional interventions. Despite decades of control efforts, the emergence of drug-resistant Plasmodium falciparum and insecticide-resistant Anopheles mosquitoes threatens to reverse recent gains. This research responds to the urgent need for sustainable and culturally relevant alternatives by exploring the therapeutic potential of Rwandan traditional medicinal plants. These indigenous remedies, long used by local healers, offer an underexplored reservoir of bioactive compounds that may provide the basis for novel antimalarial drugs.

The central hypothesis of this …

Technological Development Of In-Cell Nmr: Microfluidic, Metabolomic, And Fluxomic Approaches, Nicholas Sciolino

Electronic Theses & Dissertations (2024 - present)

In the fields of structural biology, metabolomics, and fluxomics, there is a driving, technique-based concern when it comes to high-resolution spectrometry and its marriage to biological and physiological relevance. Sample preparation often involves cellular perturbation, lysate separation schemes, combinations with non-biological reagents, and timeline slack. Conceptually, the farther we get from the cell, the greater the potential disparity between what exists in vivo and our in vitro manipulations. This is particularly true when seeking to collect data on transfected targets of interest, and on sensitive metabolic equilibria that occur on the order of minutes. The question remains: if we are …

Assessment And Health Benefit Of Vitamin C Using A549 Cell, Yetunde Adepoju

College of Graduate Studies: Theses & Dissertations

Vitamin C (ascorbic acid) is a vital micronutrient recognized for its antioxidant capacity and essential bodily functions, such as collagen formation, neurotransmitter activity, and regulation of the immune system. This study explores how vitamin C can protect and potentially heal cells under oxidative stress and inflammation, using A549 cells, a human lung epithelial cell line, as the model system. The cells were exposed to varying concentrations of vitamin C dissolved in water, DMSO, and 5% DMSO. To assess the outcome, cell viability was measured with an MTT assay. In addition, the expression of key genes related to oxidative stress and …

Approaches To The Synthesis Of Highly Substituted Arenes, Kh Tanvir Ahmed

Graduate Theses, Dissertations, and Problem Reports (ETD)

While benzene rings and their derivatives are among the most frequently encountered ring systems in natural products, pharmaceuticals, agrochemicals, dyes, and functional materials, polysubstituted arenes are relatively scarce. The analysis of FDA-approved small molecules provides valuable insights into the characteristics of successful drugs while also highlighting gaps in the availability of synthetic methods capable of efficiently accessing diverse substitution patterns on aromatic rings. Highly substituted arenes are typically synthesized through sequential modification of a pre-existing benzene core; however, this stepwise approach becomes increasingly challenging with each additional substitution. An alternative strategy involves the direct construction of benzene rings via annulation …

Rational Design Of Small Molecules Targeting Mitochondrial Redox Proteins, Matheus Barbosa Belchior

Graduate Theses, Dissertations, and Problem Reports (ETD)

Reactive oxygen species play a crucial role in many cellular processes. Despite being a natural byproduct of cellular metabolism, overexpression of these species causes damage to the cell, leading to cell dysfunction. Central to the regulation of these highly reactive molecule is the mitochondria. Impairment in its function has been associated with oxidative stress within the cell. Herein, a ligand-based and structure-based approach to design new small molecules to inhibit mitochondrial redox proteins associated with oxidative stress and reactive oxygen species. In the first project two molecules were synthesized and characterized as potential monoamine oxidase B inhibitors. Results showed two …

Towards Developing Glut2 Specific Probes For Biochemical And Biomedical Applications, Abdelrahman Ismail

Dissertations, Master's Theses and Master's Reports

Facilitated Glucose transporters (GLUTs) are membrane proteins responsible for the uptake of simple sugars and other structurally similar metabolites in all mammalian cells. One of the hallmarks of cancer is dysfunctional sugar metabolism, known as the Warburg effect, and one of the manifestations of that effect is abnormal GLUT expression. There are 14 known GLUT proteins with different expression patterns in different tissues, and tumors tend to express certain GLUTs that are not present in surrounding healthy tissue. Therefore, selective targeting of GLUTs presents a potentially powerful tool for diagnostics and treatment of cancer and other diseases. This has been …

Phytochemistry Of Dalea Candida Var. Oligophylla, Ryan E. Galperin

All Master's Theses

The focus of this project was the plant Dalea candida and its phytochemistry. The plant compounds were isolated and purified by an array of chromatographic techniques. The structures of the pure compounds were determined by one-dimensional and two-dimensional ¹H and ¹³C NMR spectroscopy, supported by infrared and ultraviolet spectroscopy, experimental and calculated circular dichroism spectroscopy, and mass spectrometry. Plant parts were worked on separately since they typically differ in content. Purified compounds will be tested for biological activities. Based on our results, eight new or known compound were isolated, specifically four new compounds and four known compounds. Compound …

Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

Sufex-Enabled Stereospecific Deoxygenative Diversification Of Alcohols, Amaechi Odoh

All Dissertations

Alcohols represent an important class of functional group in organic synthesis and medicinal chemistry, given that they are structurally diverse and prevalent in many natural products, biomolecules and renewable feedstocks. As such, they are highly attractive precursors for building-block synthesis, late-stage functionalization, and numerous synthetic transformations. However, existing strategies for the deoxygenative diversification of alcohols operate under constrained conditions, often leading to competing pathways (such as elimination), poor stereospecificity, low efficiencies, and limited substrate compatibility. To address these challenges, we have developed a conceptually novel use of sulfonyl fluorides as bifunctional reagents for the one-step deoxygenative diversification of complex alcohol …

Influence Of Glycopolymer Structure On Amphiphilic, Hybrid, Linear Branched Block Copolymer Properties For Use In Biomedical Applications, Kevin Green

Dissertations

The focus of this dissertation is evaluating and adding fundamental knowledge regarding the structure-property relations of glycopolymers used in the design of hybrid block copolymers (HBC) that are cable of self-assembling into delivery vehicles for biomedical applications. A shift to the utilization of natural materials in the design and fabrication of drug-delivery vehicles has garnered significant attention. Understanding the effects of linear glycopolymers content and composition on the resulting HBCs properties can provide valuable insight into how these materials may be tailored for use in targeted biological applications.

The first chapter introduces current literature on the need for improvement in …

Synthesis Of Photocleavable Molecules For Neurological Applications, Nishal Madujith Egodawaththa Arachchilage Don

Theses and Dissertations

In recent biomedical research, the precise control of molecular dynamics through light activation has emerged as a powerful tool, particularly in the field of neurobiology. This approach involves the use of photocleavable cages or photoprotective groups (PPGs) that are chemically tethered to biologically active molecules such as neurotransmitters or calcium chelators. These cages remain inert until exposed to specific wavelengths of light, typically in the visible range, triggering the release of the active compound with high spatiotemporal precision.

For neurotransmitter systems, such as glutamate (Glu), which plays a critical role in synaptic transmission and memory formation, researchers have developed novel …