Medicine and Health Sciences Commons^™

Identification Of More Potent And Efficacious Analogs Of The Novel Host-Derived Immunostimulant Ep67, Abdul Alshammari

Theses & Dissertations

EP67 is a human C5a-derived decapeptide agonist of C5a Receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to stimulate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Two N-alkyl amino acids Pro⁷ and N-methyl-Leu⁸ (nme-Leu⁸) within EP67 induce structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils. Cis/trans isomerization at these positions, however, likely limits the activity of EP67 and low coupling efficiency between Pro⁷ and nme-Leu⁸ increases scale-up costs for clinical use. Thus, the goals of this study were to …

Design, Synthesis, & Biological Evaluation Of Novel Het-Aromatic/Aromatic Analogs For The Treatment Of Hiv, Cancer, & Cognitive Dysfunctions, Mohit Gupta

Electronic Theses and Dissertations

Cyclophilin A are a class of peptidyl-prolyl isomerases that catalyzes isomerization of the proline residue within a protein. Cyclophilin A plays an instrumental role in the pathogenesis of HIV and HCV virus. Using structure-based drug we designed and synthesized small molecule inhibitors of cyclophilin A. These inhibitors were biologically evaluated for their ability to inhibit WT HIV-1 inhibition.

Mitogen-Activated Protein Kinase signaling cascades plays a critical role in cancer cell survival, metastasis, and chemo-resistance. The MEK5/ERK5 pathway, which is a member of MAPK signaling cascade, is involved in cell survival, anti-apoptotic signaling, angiogenesis, and cell motility. It is found to …

Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud

Theses & Dissertations

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …

Synthesis And Characterization Of Long Acting Darunavir Prodrugs, Mary Banoub

Theses & Dissertations

Patient adherence is critical for ART success to ensure adequate viral suppression, therefore, long-acting antiretrovirals are soon replacing current daily regimens. In recent years, two drugs were successfully transformed into long-acting injectables; CAB LA and RPV LA. These long-acting nanoformulations made it possible to abandon the daily pill burden, instead approximately a bimonthly injection of both drugs is enough to suppress and maintain viral load suppression. Our laboratory has been instrumental in transforming FDA-approved and experimental-HIV medications into long-acting slow effective release drugs, also known as LASER ART. LASER ART consists of slow drug metabolism and high permeability and retention …

Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Saghar Mozaffari

Pharmaceutical Sciences (PhD) Dissertations

A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R₅K]W₅, [R₆K]W₅, [R₅K]W₆, [R₇K]W₅, [R₅K]W₇, [R₆K]W₆, and [R₇K]W₇ were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively …

Synthesis Of Gadolinium-Doxorubicin Prodrug Carrying Functional Nanoceria For The Targeted Drug Delivery And Cancer Treatment, Arth Patel

Electronic Theses & Dissertations

The main focus of this research was the development of a polymer-coated nanoceria (PNC) platform to be used as a drug delivery system. Water-dispersible PNC is synthesized using a water-based alkaline precipitation method. Cerium nitrate hexahydrate and poly (acrylic acid) are used for the preparation of PNC. The synthesized PNC was characterized using ZETA, and UV- Vis characterization techniques. Polyacrylic acid (PAA)-coated cerium oxide nanoparticles fabricated for the targeted combination therapy of TNBC (MDA-MB-231) and MCF-7. Using EDC/NHS chemistry, the surface carboxylic acid groups of nanoceria was designed and synthesized with ICAM-1 antibody to target ICAM-1 overexpressing TNBC. Next, doxorubicin …

Physicochemical Properties Of Blend Poly (Vinyl Alcohol) And Sodium Alginate Membranes For Potential Application In Wound Dressings, Martha Pieper

Mechanical Engineering Theses

Poly (vinyl alcohol) (PVA) and sodium alginate (SA) are water-soluble polymers with excellent biocompatibility suitable for biomedical applications in wound dressings. In this study, pure PVA, pure SA, and blends of PVA/SA membranes were solvent cast into films followed by crosslinking in CaCl₂, boric acid, and a mixture of CaCl₂/boric acid solutions for 5, 10, and 30 minutes. Initial feasibility studies showed a strong correlation of film thickness to the observed mechanical properties. Further studies in solvent casting of blend PVA/SA films, using various polymer concentrations, yielded better film appearance with minimal physical changes after crosslinking. …

Synthesizing Galactose Modified Polymeric Nanoparticles For Biofilm Inhibition Of Pseudomonas Aeruginosa, Tyler R. Flockton

Theses and Dissertations

Treating patients with antibiotics is becoming harder with the increase in antibiotic resistance. This is due to the widespread antibiotic use in clinical and agricultural settings. With antibiotic resistance outpacing new drugs making it to the market, developing new options to treat bacterial infections is and will be important. We created sugar modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is a gram-negative opportunistic pathogen that infects its host that has a compromised immune system. This makes it one of the most significant bacterial infection in hospitals. P. aeruginosa uses biofilms as an attack mechanism …

Synthesis Of Betulinic Acid Via Baylis-Hillman Reaction, Sai Krishna Kommineni

Theses and Dissertations

Betulin is readily isolated from the bark of birch trees using simple extraction techniques and this molecule as well as its derivatives (eg. betulinic acid) exhibit impressive levels of biological activity. While it is naturally available and shows selective toxicity towards certain cancers, betulin suffers from a general lack of solubility in aqueous conditions. In this regard, we took up a project involving the synthesis of conjugates of betulin with improved solubility characteristics and we were able to identify a series of compounds that showed cytotoxicity against breast and pancreatic cancer cells.

This thesis describes our efforts on the development …

Development Of Functionalized Imidazoles As Potential Therapeutical Agents, Drew Christopher Morgan

Theses and Dissertations

Imidazoles are heterocyclic small molecules that play a major role in medicinal chemistry and drug discovery. There are several drugs in the market which contain imidazoles as the pharmacophore. Metronidazole, an imidazole containing compound, is a prominent antibiotic and antiprotozoal medication used for the treatment of a variety of infections such as amoebiasis, trichomoniasis, bacterial vaginosis, etc. The current work involves the synthesis of small molecule libraries of imidazoles derived from metronidazole using Baylis-Hillman (BH) reaction. BH reaction is a carbon-carbon bond forming reaction and involves the coupling of aldehydes or imines with activated alkenes such as acrylates, acrolein, or …

Functionalized Heterocyclics As Potential Therapeutics, Anupama Indukuri

Theses and Dissertations

Heterocyclic compounds play an important role in pharmaceutical drug development. Several natural products and biologically active compounds contain heterocyclic motifs in them. Multicomponent coupling reactions offer an excellent platform for the synthesis of diverse libraries of heterocyclic compounds. We have been working on the synthesis of novel heterocyclic small molecules utilizing reactions such as Baylis-Hillman reaction, Passerini reaction, Click reaction, reductive amination aldol condensation, etc.

In the current project, we prepared three series of heterocyclic compounds using Passerini and Baylis-Hillman reactions as key steps. Owing to the importance of heterocyclic chemistry in drug discovery and the ease of synthesis, the …

Dual Inhibition Of The Pi3k/Akt And Mek5/Erk5 Pathways For The Treatment Of Breast Cancer, Thomas Douglas Wright

Electronic Theses and Dissertations

Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects …

Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Anti-Cancer Agents With Combination Chemotherapeutic Potential Or Targeted One Carbon Metabolism Inhibition And Anti-Opportunistic Agents, Arpit Doshi

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic, bicyclic and tricyclic pyrimidine-based heterocycles as a) single agents with combination chemotherapy potential having dual antiangiogenic effects and cytotoxic effects or b) one-carbon metabolism inhibitors for targeted tumor therapy; or c) selective Pneumocystis jirovecii (pj) dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization or thymidylate synthase as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), epidermal growth …

Synthesis And Characterization Of Long-Acting Rilpivirine Prodrugs, James R. Hilaire

Theses & Dissertations

Antiretroviral therapy (ART) requires lifelong daily dosing to suppress viral replication, restore or maintain immune function and improve quality of life. As an alternative, long-acting (LA) antiretrovirals (ARVs) aim to deliver therapeutic drug concentrations over an extended period, ultimately requiring monthly or even more extended dosing intervals. Specifically, the success of recent clinical trials examining LA cabotegravir and rilpivirine (CAB and RPV LA) highlight the advent of these novel HIV-1 therapeutics. Further optimization of LA dosage forms are required and rests upon improving dosing frequency, injection volumes and tissue distribution to viral compartments. To this end, we report the synthesis …

Altering The Regiospecificity Of C6 Indole Prenyltransferase Enzymes Towards Drug Development, Ahmed R. Aoun

Pharmaceutical Sciences (MS) Theses

Prenyltransferase (PT) biocatalysts are late-stage tailoring enzymes that modify natural products. PTs catalyze the attachment of prenyl moieties to natural product acceptors using pyrophosphate donors. This prenyl modification in small molecules leads to changes in structural and biological activities. Understanding the structural insights as well as the mechanisms by which PTs function allows us to utilize PTs as a unique approach towards drug development. PriB PT is an example of aromatic PTs that has been characterized previously as a L-tryptophan (L-Trp) C6 C-prenyltransferase (C6-C-PT). Analysis of PriB binding pocket, highlighted key residues that might play an important …

Study Of Blood Viscosity With Added Sodium Nitrate And Temperature Variance: A Potential Therapy To Regulate Blood Flow After Induced Hypothermia, Brianna Munnich

Pence-Boyce STEM Student Scholarship

The human body has natural systems for vasodilation which are fueled by nitric oxide production, but in cases of cardiac disfunction and stress nitric oxide can be inhibited. In this study, nitric oxide was studied as a mediator for the blood rush experienced from the warming after induced hypothermia. Nitric oxide (NO) was introduced through sodium nitrate, which was aimed to reduce the speed and turbulence of blood flow through interaction between NO and the active site of hemoglobin. A viscometer was used to examine the rate of blood flow, while the temperature was varied to simulate the conditions of …

Modification And Characterization Of Chloro-Sugar Derivatives As Anti-Bacterial Agents, Mansi Jani

Theses and Dissertations

Sucralose is an artificial sugar substitute which is most commonly used sweetener among other artificial sweeteners. It is derived from sucrose through a complex chemical process that selectively substitutes three atoms of chlorine for three hydroxyl groups on sucrose molecule, which have shown some inhibition of bacterial growth in gut. The goal of the project was to substitute halide in sucralose in a way that it sustains potential anti-bacterial activity along with sweetening effect, which can be then incorporated into mouthwash formulation. Sucralose is very stable molecule and it also has other physico-chemical advantages which are suitable for our anticipated …

Development Of Approaches Of Tumor Trapping Enhanced Bb2r-Targeted Radiopharmaceuticals For Prostate Cancer, Wenting Zhang

Theses & Dissertations

The Gastrin-Releasing Peptide Receptor (BB2r) has been intensively investigated as a cancer target over the years. Numerous diagnostic and therapeutic BB2r-targeted agents have been developed for various solid tumors, including prostate cancers, due to the high expression level of BB2r on neoplastic relative to normal tissues. The development of those targeted agents have mainly utilized the modified c-terminal of bombesin(BBN), a peptide that has nanomolar binding affinity to human BB2r. However, a major issue that hinders the clinical translational potential of low-molecular weight, receptor-targted agents, is their short residence time at tumor tissues due to the intrinsically high diffusion and …

Iron-Containing Nanoparticles For The Treatment Of Chrionic Biofilm Infections In Cystic Fibrosis, Leisha M. A. Martin

Nanoscience and Microsystems ETDs

Cystic fibrosis (CF) is the most common genetic disease resulting in the morbidity and mortality of Caucasian children and adults worldwide. Due to a genetic mutation resulting in malfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, CF patients produce highly viscous mucus in their respiratory tract. This leads to impairment of the mucociliary clearance of inhaled microbes. In addition to reduced microbial clearance, anoxic environmental conditions in the lungs promote biofilm-mode growth of the pathogenic bacterial species Pseudomonas aeruginosa. Chronic infections of P. aeruginosa begin in early childhood and typically persist until respiratory failure and death result. The …

Meta-Analysis To Identify And Evaluate Factors Associated With Regulatory Approval Of Orphan Drugs (Od) To Develop An Algorithm For Predicting Regulatory Approval (Success) And To Develop A Standardized Tool To Improve Orphan Drug Portfolio Decision-Making, Milky C. Florent

Seton Hall University Dissertations and Theses (ETDs)

Background and Purpose of the Study: Developed an algorithm (AODI) for predicting probability of regulatory success (PRS) for new orphan drugs after phase II testing has been conductedwith the objective of providing a tool to improve drug portfolio decision-making.Methods: Examined 132 studies from recent publications (2005 onwards). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Meta-analysis and meta-regressions were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors.Results: Found that a simple three-factor model (disease prevalence, clinical trial duration and clinical trial …

Synthesis Of Novel Library Of Cyanopyrrolidinyl Beta-Amino Alcohols And Matrine Alkaloids, Xiaotian Chen

Theses and Dissertations

Cyanopyrrolidines and beta-Amino alcohols are molecular scaffolds that are highly found in commercially available drugs. We developed a multi-step synthetic method to form a novel library of compounds as inhibitors that share both scaffolds toward potent and selective diabetes therapeutics. Despite the ease for the synthesis of Cyanopyrrolidines, the difficulty of forming high selective beta-Amino alcohols is challenging. We successfully find the best condition for the preference of highly selective mono-alkylation and double-alkylation products and produce them with high yield.

Matrine is an alkaloid found in plants from the genus Sophora and can produce some pharmacological effects such as anti-cancer …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

Semisynthetic Aurones: A Family Of Newly Discovered Tubulin Inhibitors As Antineoplastic Agents, Yanqi Xie

Theses and Dissertations--Molecular and Cellular Biochemistry

Aurones belong to an uncommon class of plant flavonoids that provide the bright yellow coloration of some ornamental flowers and that possess a range of biological activities. Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the biologically active analogs developed in the course of this dissertation work were (Z …

The Development Of Novel Proteasome Inhibitors For The Treatment Of Multiple Myeloma And Alzheimer’S Disease, Min Jae Lee

Theses and Dissertations--Pharmacy

Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.

In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a …

Computational Modeling Guided Discovery Of Novel Inhibitors Of Mpges-1 And Butyrylcholinesterase As Drug Candidates, Shuo Zhou

Theses and Dissertations--Pharmacy

Ever since the advent of computer-aided drug design (CADD), in silico simulation methods have greatly accelerated the drug discovery process and lead to the discovery of numerous drug candidates. With the exponential growth of computational power, we nowadays simulate biologic systems at a scale unimaginable a decade ago and thus provides perspectives for drug design. In this dissertation research, combining in silico simulation methods like molecular docking and molecular dynamics (MD) simulation with organic synthesis, in vitro/in vivo experiments and clinical data mining, we developed new drug discovery strategies. These strategies were applied in our drug discovery projects and led …

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 …

Intrapulmonary Inoculation Of Multicellular Tumor Spheroids To Construct An Orthotopic Lung Cancer Xenograft Model That Mimics Four Clinical Stages Of Non-Small Cell Lung Cancer, Yingbo Huang

University of the Pacific Theses and Dissertations

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen …

Development And Characterization Of Ldv Peptide Targeted Nanocarriers For Paclitaxel Delivery: A Comparative Study Of Micelles, Liposomes And Solid Lipid Nanoparticles, Poonam Dattani

University of the Pacific Theses and Dissertations

Nanocarriers have been established as delivery vehicles to target cancer tumors. However, premature drug leakage is one of the major reasons for inefficient drug delivery of nanocarriers to the tumor. Drug diffusion out of the nanocarriers or destabilization of drug loaded nanocarriers by physiological interactions with blood cells, serum proteins, and cell membranes upon systemic administration contribute to premature drug release. In this study, targeted micelles, liposomes and solid lipid nanoparticles (SLNs) of similar composition were prepared and characterized to compare physicochemical characteristics, in vitro stability, in vitro release rates in release media and in vivo performance. Peptide Amphiphiles (PAs) …

Investigating The Effect Of Rutaecarpine On The Benzo[A]Pyrene-Induced Dna Damage In Vitro, You Li

University of the Pacific Theses and Dissertations

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl …

Development Of A New Class Of Ligand-Targeted Chemotherapeutics With Enhanced Safety And Efficacy Profile, Arindom Pal

University of the Pacific Theses and Dissertations

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of …