Medicinal and Pharmaceutical Chemistry Commons^™

Phytochemical And In-Vitro Cytotoxic Analyses Of Flavonoid Species Isolated From Chromolaena Leivensis, Luke A. Bryant

Electronic Theses and Dissertations

As a leading cause of death worldwide, cancer and its treatments remain a primary source of interest among researchers. Modern studies are looking into bioselective cytotoxicity to create new chemotherapies that do not have the same harsh side effects as those we use today. Natural product research has a promising future for the development of such treatments. Specifically, polar flavonoids may be the key to a bioselective treatment. Such flavonoid species are native to plants, often within flower petals or within the body. A natural antioxidant, they are designed not to harm healthy cells. This study focuses on the plant …

Synthetic Explorations Towards Phenyl Benzazepine-Inspired Scaffolds And Synthesis Of Minor Cannabinoid Derivatives, Vishwashiv Kumar Emogaje

Theses and Dissertations

D1R is a compelling therapeutic target for correcting dopaminergic imbalances. However, existing ligands exhibit suboptimal pharmacokinetic properties. As such, we synthetically explored untouched structural modifications to the phenyl benzazepine scaffold. Cannabinoid-based molecules also display potential to treat neurological maladies and cancer. We synthesized Cannabichromene derivatives and uncovered enhanced anticancer activities.

Protein Allostery Probed By Ligands Across Sites, Virgil A. Woods

Dissertations, Theses, and Capstone Projects

Allostery is a pervasive regulatory principle throughout biology, yet the structural pathways by which distal inputs alter active‑site chemistry within protein structures remain incompletely defined and exploited. This dissertation uses protein tyrosine phosphatase 1B (PTP1B) as a tractable model to map those pathways with complementary experimental and computational tools. I integrate high‑resolution hydrogen-deuterium exchange mass spectrometry (HDX-MS), room-temperature crystallography, NMR, steady-state kinetics, crystallographic pseudo-ensembles, and machine-learning-guided ligand discovery. The working premise is that regulation reflects redistribution within a conformational ensemble rather than a binary switch. That orthogonal perturbations by small molecules, mutations, and protein partners can be used to both …

Evaluation Of Peptides And Peptide–Doxorubicin Conjugates Designed And Synthesized For Targeting Triple-Negative Breast Cancer Via Cell-Surface Receptors, Shih-Jing (Jane) Yao

Pharmaceutical Sciences (PhD) Dissertations

A significant problem faced in oncology is the lack of chemotherapeutic agents that are tumor site-specific, resulting in reduced therapeutic efficacy and unintended infliction of harm to surrounding healthy tissues and cells that often lead to serious side effects. Current strategies being explored to circumvent this issue aim to refine delivery of  chemotherapeutic agents specifically to tumor sites, which may be achieved via conjugation of these agents to biomarker-specific ligands. This forms the foundation of ligand-targeted drug delivery. Among different breast cancers, treatment of the triple-negative breast cancer (TNBC) subtype has been particularly challenging, largely due to the absence of …

Evaluation Of The Physical Properties And In Vitro Safety Of Chitosan-Quercus Infectoria Topical Gel, Rani Naga Rakshitha Tillapudi

Theses, Dissertations and Capstones

Due to ongoing inflammation, inadequate blood flow, oxidative stress, and reduced tissue regeneration, chronic diabetic wounds heal slowly, which is a serious health concern. It is important to examine novel strategies that tackle these issues because conventional treatments frequently fail. Therefore, this study examined the physical properties and biocompatibility of a novel topical gel formulated with chitosan and Quercus infectoria gall extract.

Over 28 days, pH, spreadability, texture, homogeneity, color, and drug concentration were assessed. UV-visible spectrophotometry and FTIR analysis were used to establish chemical stability. The MTT assay was used to test its safety in human dermal fibroblast adult …

Nanocomposite Mediated Delivery Of 5-Fluorouracil Using Silver Nanoparticles To Promote Wound Healing, Kamal Nath Kasi

Theses, Dissertations and Capstones

Chronic wounds, particularly in diabetic patients, remain a significant clinical challenge due to the complex interaction of persistent infection, chronic inflammation, and impaired cellular regeneration. Conventional drug therapies often fail to achieve effective treatment due to rapid drug degradation, poor targeting, and localized toxicity. This study explores a nanotechnology-based approach by developing and evaluating 5-FU loaded AgNP (AgNP–5FU) as a controlled drug delivery system. AgNP (AgNP) were synthesized and characterized using scanning electron microscopy (SEM), energy dispersive X-ray (EDX) analysis, particle size, and zeta potential analysis, while Fourier Transform Infrared Spectroscopy (FTIR) analysis suggested possible interaction between 5-FU and the …

Development And In Vitro Characterization Of 5-Fluorouracil–Loaded Plga Nanoparticles For Controlled Drug Delivery, Kavya Yandapalli

Theses, Dissertations and Capstones

Non-Alcoholic Fatty Liver Disease (NAFLD) is a progressive metabolic disorder characterized by excessive lipid accumulation in hepatocytes and chronic inflammation. Nanoparticle-based drug delivery systems offer a promising strategy to enhance therapeutic efficacy while minimizing systemic toxicity. The objective of this study is to formulate and characterize 5-FU–loaded PLGA nanoparticles and evaluate their in vitro performance. 5-FU–loaded PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The nanoparticles were characterized by particle size, polydispersity index, zeta potential and SEM. Drug encapsulation efficiency, loading capacity and in vitro drug release studies were conducted. The formulated nanoparticles exhibited sizes within the …

Development Of Tunable Rose Bengal Based-Nanogumbos As Potential Selective Chemotherapeutic Agents, William J.A. Russell

Honors College Theses

As cancer remains one of the greatest threats to the global population, the development of chemotherapeutic agents that are selective and tunable is of critical importance. Herein, a series of Rose Bengal (RB)-based GUMBOS, a group of uniform materials based on organic salts, were synthesized via counterion exchange between [Na]₂[RB] and three organic cations: tetrabutylphosphonium bromide [TBP][Br], tetraphenylphosphonium chloride [TPP][Cl], and 1-dodecyl-3-methylimidazolium chloride [C₁₂MIm][Cl]. The resulting GUMBOS were characterized through FT-IR, ESI-MS, NMR, and UV-Vis Spectroscopy. Partition coefficient studies indicated all GUMBOS exhibited hydrophobic physiochemical characteristics. These hydrophobic RB-based GUMBOS …

Developing Curcumin Analogues For Treating Breast Cancer, Tulasi Laxmi Nutalapati

Theses, Dissertations and Capstones

Breast cancer is still one of the most common types of cancer and one of the most common causes of cancer-related deaths in women around the world. Despite significant advances in early detection and treatment strategies, drug resistance, systemic toxicity, and poor outcomes in aggressive subtypes continue to limit the overall effectiveness of cancer therapy. Natural compounds have become promising anticancer agents because they can target many different things and are not very toxic. Curcumin has shown promise as an anticancer drug, but it cannot be used in the clinic because it does not absorb well, breaks down quickly, and …

Metabolomics Driven Discovery Of Bioactive Natural Products Leads From Marine And Terrestrial Sources For The Development Of Analgesics, Sahar Mofidi Tabatabaei

University of Kentucky Doctoral Dissertations

Natural products remain a rich source of structurally diverse bioactive compounds for drug discovery, particularly for pain therapeutics. However, the chemical complexity of natural product extracts presents significant challenges for the efficient identification and prioritization of bioactive metabolites. This dissertation integrates untargeted LC-MS/MS-based metabolomics, molecular networking, classical natural products chemistry, and neurobiological assays to accelerate the discovery of analgesic lead compounds targeting the emerging pain-associated receptor σ₂R/TMEM97.

An untargeted metabolomics workflow was developed to systematically profile complex biological extracts and guide bioactive compound isolation. High-resolution LC-MS/MS data were analyzed using molecular networking (GNPS/GNPS2) to visualize chemical space, dereplicate known metabolites, …

Investigating The Role Of Traditional Chinese Herbal Medicine For Cancer Symptom Management In Older Adults: A Rapid Review, Isabelle C. Karshner

Honors Undergraduate Theses

Background: Patients with cancer often experience symptoms related to disease, complications, and treatment. One potential method of alleviating these symptoms is traditional Chinese herbal medications (TCHM). This rapid review explores the role of traditional Chinese herbal medications in treating cancer-related symptoms in older adults.

Purpose: The purpose of this rapid review is to gain and provide a better understanding of the effects of TCHM on cancer-symptom management in the older adult population. This review explores the association between TCHM and effects on cancer symptoms in older adults, including interactions, toxicity, and signs/symptoms of TCHM use that may be useful information …

Development Of Self-Assembled Polymeric Polyplexes For Microrna Delivery: Toward Treatment Of Alcohol-Associated Liver Disease, Marjina Akter Kalpana

Theses & Dissertations

Self-assembled polymeric polyplexes have the potential to serve as an RNA interference (RNAi) delivery platform for the combined inhibition of CXCR4 and miR-155 in the treatment of alcohol-associated liver disease (AALD). A central challenge in RNA delivery is balancing the extracellular stability of polyplexes, cellular uptake, and intracellular release of RNA cargo. We developed polymeric polyplexes using the CXCR4-antagonist polymer PAMD, designed to target CXCR4 on activated hepatic stellate cells (HSCs) and deliver therapeutic miRNA to activated Kupffer cells (KCs) in fibrotic liver. We improved the polyplexes by cholesterol modification of PAMD and by PEGylation of PAMD-Ch. The cholesterol modification …

Study Of Peptide Amphiphiles As Antimicrobial Agents, Aramis J. Pereira

Theses & Dissertations

The global antimicrobial resistance (AMR) crisis presents a severe public health threat, with drug-resistant infections now the third leading cause of mortality worldwide. This escalating problem, driven by the rapid proliferation of multidrug-resistant organisms (MDROs) like the "ESKAPE" pathogens, severely limits treatment options and imposes substantial economic burdens. The crisis is further exacerbated by a limited pipeline of new antimicrobial agents, as most recently approved drugs are modifications of existing classes rather than novel compounds. Peptide amphiphiles (PAs) offer a promising alternative due to their membrane-targeting mechanism, which reduces the likelihood of resistance development. These molecules are amphiphilic and positively …

Determining The Bioaccumulation Of Minor Cannabinoids In Zebrafish Larvae, Kamdyn A. Holt

Honors Theses

Due to the increasing prevalence of cannabis product availability and usage in the modern United States, particularly among pregnant individuals, evaluating the bioaccumulation of minor cannabinoids to further understand the adverse effects of cannabinoids during early development is critical. This study quantitated the uptake of eight minor cannabinoids ((∆8-tetrahydrocannabinol (∆8-THC), ∆9-THC, ∆10-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), tetrahydrocannabivarin (THCV), and hexahydrocannabinol (HHC)) in zebrafish larvae following water-borne 2 µM exposures from 6 to 96 hours post fertilization (hpf). Larvae were homogenized at 96 hpf and analyzed using a gas chromatography- mass spectrometry (GC-MS) method developed in this study. Bioconcentration …

In Vivo Evaluation Of Novel Nanoparticles And Repurposed Pharmaceuticals To Combat Antimicrobial Resistance, Sarah E. Evans

Theses, Dissertations and Capstones

In a 2019 report by the Centers for Disease Control and Prevention (CDC), infections resistant to antibiotic treatment amount to about three million infections and 48,000 deaths. Antimicrobial resistance is an escalating global threat as existing antibiotics lose efficacy over time. The project described is focused on partnering with pharmaceutical researchers and producers to test new nanoparticle-based or repurposed compounds. The central hypothesis of this thesis is that pharmaceutical formulations such as nanoparticles may provide a cost-effective means of combating the emerging antimicrobial resistance. The nanoparticle compounds allowed for a wide range of customization for the pharmaceutical design, since the …

Evaluation Of Disulfiram And Derivatives As Antimicrobial Adjuvants, Surya Bhaskar Karuturi

Theses, Dissertations and Capstones

Disulfiram (Antabuse) is an oral drug used for the treatment of alcohol dependence. Previous studies showed that disulfiram has antibiotic activity on multidrug-resistant bacteria. Here disulfiram was further evaluated for its ability to increase the potency of existing antimicrobials against the bacteria and yeast by acting as a drug adjuvant. Microbial cultures were treated with antibiotic or antifungal drugs in combination with disulfiram and its derivatives to determine whether potency is increased. The structure activity relationship (SAR) of disulfiram analogs was assessed against a triazole resistant Aspergillus panel. It showed that the shorter chained analogs of disulfiram are more potent …

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 …

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 …

Impact Of Tetrahydrocannabinol (Thc) On Daphnia Magna Heart Rate, Ashley Cosgrave

Williams Honors College, Honors Research Projects

Marijuana (Cannabis) is currently federally illegal within the United States and classified as a Schedule I drug. This leaves a large research gap on the impacts of Tetrahydrocannabinol (THC) use. Daphnia magna are frequently used as a model organism for the human heart and toxicology screenings due to their myogenic heart, similarities in physiological pathways, and sensitivity to toxins. As such, in order to bridge the research gap and uncover potential use of Daphnia magna as a model organism for humans in regard to impact on heart rate, we hypothesized that if Daphnia magna possess CB1 receptors or an equivalent …

Synthesis Of Tu100 Analogs And Biological Assays, Feyisope Tonye Oladapo

College of Graduate Studies: Theses & Dissertations

TU100 (14-methyl-5H-5,12-epiminobenzo[4,5]cyclohepta[1,2-b]naphthalene-6,11,13(12H)-trione) exhibits exceptional chemotherapeutic properties. It operates via a distinct mechanism that triggers cell death to create cytotoxic effects while concurrently inhibiting topoisomerase I and II. Its efficacy rivals that of well-known chemotherapeutic drugs like Daunorubicin. The distinctive characteristics of TU100 have led to initiatives aimed at creating structurally similar compounds to discover even more effective bioactive alternatives.

The analog synthesis incorporated quinoxaline or its derivatives (diphenyl quinoxaline, dipyridinyl quinoxaline, and dibenzophenazine-10,13-dione) that have been shown to have promising chemotherapeutic effects. Synthesizing the hetero naphthoquinones required a multi-step synthetic process, so quinoxaline/ derivatives intermediates are first prepared, then the …

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 …

Development Of Novel Carbohydrate-Based Nanoparticles For Precision Drug Delivery, Krystal Ann Hughes

Graduate Theses, Dissertations, and Problem Reports (ETD)

Nanoparticle-based drug delivery has made tremendous advancements in the last decade. However, several critical factors, including precision drug delivery at the site of interest, long-term storage stability, and controlling release profiles of drugs in the systemic circulation, need to be addressed for successful clinical translation of nanomedicine. This dissertation presents novel carbohydrate-based nanoparticles that achieve precise intracellular delivery and therapeutic release at the disease site. We present the formulation and optimization of polymeric and polymer-lipid hybrid nanoparticles that enable precision intracellular delivery and passive accumulation of therapeutics in the bone marrow. Intracellular delivery is highly impactful and sought after. One …

Design, Synthesis, And Characterization Of Multi-Targeting Pyrrolopyrimidine Antifolates As Potential Single Agent Chemotherapeutic Entities, Tejashree Magdum

Electronic Theses and Dissertations

In cancer chemotherapy, the currently marketed antifolates have two major disadvantages: dose-limiting toxicities to normal tissues and susceptibility to drug resistance. These are due to their major transport by the ubiquitously expressed transporter and mutagenesis in enzymes present in cancer cells. This thesis describes an introduction, background, and research progress in antimetabolites-antifolates designed to multi-target (a) one-carbon metabolism and de novo nucleotide synthesis pathway and (b) target overexpressed transporter in cancer cells for selective tumor-targeting.

Cancer cells transport folate through three transporters: ubiquitously expressed reduced folate carrier (RFC), limitedly expressed proton-coupled folate transporter (PCFT), and folate receptors (FRs). The research …

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 …

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 …

Incorporating Solvation Thermodynamic Mapping In Computer-Aided Drug Design, Yeonji Ji

Dissertations, Theses, and Capstone Projects

Advancements in computational techniques have revolutionized structure-based drug design, substantially improving the efficiency and effectiveness of the drug discovery process by reducing time, costs, and labor requirements. These advancements include various methods, such as investigating small molecule ligands binding to proteins, exploring alternative protein conformations, and solvation mapping on the protein surfaces. Among these methods, understanding the correlation between protein-ligand binding and the role of solvation is important.

A fundamental concept in protein-ligand binding is shape and electrostatic complementarity, which is complicated by the inherent flexibility of proteins. In the absence of small molecule ligands, proteins are complementary to surface …

Potent And Selective Small Molecule Mcl-1 Inhibitor Demonstrates Anti-Myeloma Activity And Overcomes Chemotherapy Resistance, Omar Sami Faleh Al-Odat

Theses and Dissertations

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive” which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates …

Design, Synthesis, And Biological Evaluation Of Novel Heterocyclic Compounds For The Treatment Of Cancer And Neurodegenerative Disorders, Saloni Patel

Electronic Theses and Dissertations

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment, mostly in older people. It is the leading cause of dementia in late adult life. The hallmarks of AD include neuronal loss, neuroinflammation, a build-up of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles, and extracellular neuritic plaques. Current treatment, although useful, is not adequate. Identification of therapeutic agents with the potential to alter the progress of AD is a high priority. Recent studies suggest that the Sigma-2 receptor is an attractive target for the development of disease-modifying AD drugs. Preventing the binding of Sigma-2 receptors …

Targeting Cancer- One Carbon At A Time: Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Cancer Chemotherapeutics, Md Junayed Nayeen

Electronic Theses and Dissertations

With over 6 million death counts, cancer is the second leading cause of death in the United States. Lung cancer was the leading cause of cancer death, accounting for 23% (136,084 death count) of all cancer deaths. Other than that, colon and rectal (9%, 51,869 death count), pancreas (8%, 46,774 death count), female breast (7%, 42,275 death count), prostate (5%, 32,707 death count), and liver and intrahepatic bile duct (5%, 28,227 death count). Other cancers individually accounted for less than 5% of cancer deaths. Although cancer death rates decreased about 27% from 2001 to 2020, the therapeutic options are limited …

Amphipathic Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Jonathan Moreno

Pharmaceutical Sciences (PhD) Dissertations

Amphipathic Hybrid Cyclic-Linear Peptides as a Drug Delivery System by Jonathan A. Moreno Peptides

[RW]₄ and [R₅W₄] have been previously identified as molecular transporter Cell Penetrating Peptide (CPP) and antimicrobial agents, respectively. These peptides consisted of alternating and non-alternating arginine (R) as positively charged residues and tryptophan (W) as hydrophobic residues. Herein we report the synthesis of two hybrid amphipathic cyclic-linear cell-penetrating peptides [RW]₄K-AH135 (1) and [R₅W₄]K-AH135 (2) composed of [RW]₄ and [R₅W₄] and a linear peptide AH-135 (Ac)NH-RWLRRWLRWWRR-COOH. The …