Medicinal-Pharmaceutical Chemistry Commons^™

Design And Synthesis Of Analogs Of Myo-Inositol, Serine, And Cysteine To Enable Chemical Biology Studies, Tanei J. Ricks

Doctoral Dissertations

Phosphorylated myo-inositol compounds including inositol phosphates (InsPs) as well as the phosphatidylinositol polyphosphate lipids (PIP_ns) are critical biomolecules that regulate many of the most important biological processes and pathways. They are aberrant in many disease states due to their regulatory function. The same is true of the phospholipid phosphatidylserine (PS) which can serve as a marker to begin apoptosis. However, the full scope of activities of these structures is not clear, particularly since techniques that enable global detection and analysis of the production of these compounds spatially and temporally are lacking. With all of these obstacles in …

Green Chemistry Oxidative Modification Of Peptoids Utilizing Bleach And Tempo, Jesse Leland Roberts

Graduate Theses and Dissertations

Biotherapeutic drugs, derived from biological molecules such as proteins and DNA, are becoming an integral and exceptionally critical aspect of modern medicine. Compared to common pharmaceutical drugs, biotherapeutics are much larger in size and have greater target specificity, allowing them to treat many chronic diseases ranging from cancer to rheumatoid arthritis. The major issue with protein based therapeutics is that they readily undergo proteolysis, or enzymatic degradation, when administered through subcutaneous injections. Traditionally, biotherapeutic modification procedures have centered on the use of PEG derivatives. This process, called PEGylation, is unfavorable due to the increases in molecular weights of the proteins …

Substituted Hydroxylamines As Nitrogen Transfer Reagents: Direct Synthetic Pathways To Structurally Rich Heteroatomic Scaffolds, Dylan John Quinn

Theses and Dissertations

Nitrogen is found in virtually all valuable chemical compounds. The abundance of atmospheric nitrogen however, is rendered inaccessible because of the strong N-N triple bond, ultimately preventing its practical utilization in synthetic organic synthesis. The development of powerful nitrogen transfer reagents, such as substituted hydroxylamine derivatives, have played an important role in the introduction of nitrogen into valuable chemical scaffolding.

Herein is reported the methodological development of synthetic nitrogen placement into a range of valuable heteroatomic compounds. This work shows that O-Substituted Hydroxylamine can be used to furnish small heteroatomic compounds, particularly nitriles. Whereas, N-Substituted Hydroxylamine can be employed to …

Nanoparticle As Supramolecular Platform For Delivery And Bioorthogonal Catalysis, Gulen Yesilbag Tonga

Doctoral Dissertations

Nanoparticles (NPs) are being investigated widely for many applications including imaging, drug delivery, therapeutics, materials, and catalysis due to their unique and tunable physical and chemical properties. Among NPs, gold nanoparticles (AuNPs) have attracted great attention due to ease of synthesis and surface functionalization, inertness of the core, biocompatibility, and functional versatility. Introducing supramolecular chemistry into the nanoparticle-based platforms brings out controllable properties, dynamic self assembly processes, and adjustable performance. My research has focused on the synthesis of AuNPs bearing different surface functionalities and their host-guest interactions with synthetic small molecules or commercially available hydrophobic catalysts for delivery and therapeutic …

Development Of Novel Alkaloid Derivatives For The Treatment Of Chronic Myeloid Leukemia, Lindsay Michelle Renn

Theses and Dissertations

The majority of chronic myeloid leukemia (CML) patients can be treated with and respond to imatinib mesylate (Gleevec). Imatinib is known to inhibit BCR-ABLl kinase activity, and is effective for the treatment of the majority of CML patients. Multiple mutations have been found in patients resistant to imatinib treatment, including many located in the BCR-ABLl tyrosine kinase domain (e.g. E255K and T315I). Matrine is a bioactive alkaloid from Sophora flavescens and has been shown to inhibit several types of cancers and is used in Chinese medicine. The goal of this study is to develop new matrine derivatives that inhibit growth …

Nucleotide-Dependent Preferential Localization Of Ras In Model Membranes With Lipid Raft Nanodomains, Anna Shishina

Dissertations (1934 -)

Membrane proteins constitute a third of all proteins in the cell and more than 50% of drug targets. However, the analysis of membrane proteins has many challenges owing to their partially hydrophobic surfaces, flexibility and lack of stability. One example of an essential membrane protein is Ras superfamily. Ras is a small monomeric GTPase involved in regulation of cell growth, proliferation and differentiation. Therefore, Ras and its effectors are among the most important targets for cancer therapy. A detailed knowledge of the processes occurring during signal propagation via Ras might help to elucidate the mechanisms of the involved signal cascades. …

Poly(Ethyl Glyoxylate) Solid-Core Particles For Drug Delivery, Michael Thomas Gambles

Electronic Thesis and Dissertation Repository

The ability to trigger the degradation of polymeric nanoparticles (NPs) by a specific stimulus can provide a method of improved drug targeting and selective release capabilities in vivo. The challenge for most polymeric drug delivery systems remains the necessity for many stimuli events to trigger the release of cargo. Polymeric nanotechnology containing “self-immolative polymers” looks to alleviate the reliance on high concentrations of stimuli by undergoing complete end-to-end depolymerization via a single stimulus-mediated reaction of an end-cap. Herein, NPs were developed using poly(ethyl glyoxylate) (PEtG) blended with poly(d,l-lactic acid) (PLA) to encapsulate a hydrophobic cargo to be released upon …

Crystal Engineering Of Active Pharmaceutical Ingredients With Low Aqueous Solubility And Bioavailability, Jenna M. Skieneh

Electronic Thesis and Dissertation Repository

Approximately 75% of new molecular entities approved by the Food and Drug Administration (FDA) for use in the pharmaceutical industry are found to have poor aqueous solubility. This undesirable attribute leads to consequences such as higher doses required to reach therapeutic levels, greater vulnerability to food effects, lesser fraction absorbed in the small intestine and damage to the environment due to increased quantity of excretion. The addition of an excipient (i.e. a FDA approved inactive ingredient) to the molecular structure of an active pharmaceutical ingredient (API) through intermolecular bonding is of growing interest because the properties of the API can …

A Novel Method For Synthesis Of Hydroxytyrosol, Emmanuel Onobun

Electronic Theses and Dissertations

Hydroxytyrosol, 3,4-dihydroxyphenolethanol, a naturally occurring polyphenol most common in olive tree (Olea europaea), is one of the most effective member of the polyphenols family, because of its remarkable antioxidant activity, its ability to inhibit oxidation of low density lipids (LDL), and its protection against DNA oxidative damage. Hydroxytyrosol, which is widely used in cosmetics and food supplements industries, can be purchased as an olive oil extract that contains low concentration of hydroxytyrosol besides other polyphenols. The price and low natural abundance of hydroxytyrosol make alternative synthetic sources very attractive. In this research, a novel method for the synthesis of pure …

Analytical Methods To Support Design And Optimization Of Protein Drug Conjugate: Focusing On Haptoglobin-Hemoglobin Complex As A Drug Carrier, Shengsheng Xu

Doctoral Dissertations

Acquired immunodeficiency syndrome (AIDS) remains one of the most serious public health challenges and a significant cause of mortality for certain populations. Despite the large number of antiretrovirals (mostly nucleotide and nucleoside analogs) developed in the past two decades, the inability of small molecule therapeutics to target HIV reservoirs directly creates a significant obstacle to their effective utilization. Indeed, achieving the desired therapeutic effect in the absence of the effective targeted delivery must rely on dosage escalation, which frequently causes severe toxicity. This problem may be solved by conjugation of antiretroviral agents to endogenous proteins (e.g., hemoglobin haptoglobin complex) that …

Rational Drug Design Directed At Blocking The Initial Signaling Events In Lipopolysaccharide-Induced Sepsis., Christopher A. Tipton

Theses

Systemic Inflammatory Response Syndrome (SIRS) is classified as an immune system response to an infectious state. If left untreated, SIRS leads to sepsis, septic shock, end-organ dysfunction, and death. As a patient progresses through these stages, associations of acute respiratory distress, disseminated intravascular coagulation, and acute renal failure persist, resulting in millions of deaths annually. Lipopolysaccharide (LPS), a bacterial endotoxin, is released into the blood stream, triggering SIRS. LPS is found in the outer cell-wall of Gram-negative bacteria and is responsible for initiation of a devastating cytokine storm. One of the regions of LPS, lipid A, is a polyacylated glucosamine …

Design And Synthesis Of Selective Estrogen Receptor Β Agonists And Their Pharmacology, K. L. Iresha Sampathi Perera

Dissertations (1934 -)

Estrogens (17β-estradiol, E2) have garnered considerable attention in influencing cognitive process in relation to phases of the menstrual cycle, aging and menopausal symptoms. However, hormone replacement therapy can have deleterious effects leading to breast and endometrial cancer, predominantly mediated by estrogen receptor-alpha (ERα) the major isoform present in the mammary gland and uterus. Further evidence supports a dominant role of estrogen receptor-beta (ERβ) for improved cognitive effects such as enhanced hippocampal signaling and memory consolidation via estrogen activated signaling cascades. Creation of the ERβ selective ligands is challenging due to high structural similarity of both receptors. Thus far, several ERβ …

Synthesis And Identification Of An Investigational Essential Precursor Compound For The Purpose Of The Development Of A Vaccine Treatment Against The Peanut Allergy, Thomas F. Anguella

Theses and Dissertations

Presented in this master's thesis are several studies carried out to determine the viability of several allergoid candidates utilizing the major peanut allergen Ara h 2. The Ara h 2 allergen protein appears naturally as a doublet when observed by gel electrophoresis, SDS-PAGE. Optimization of allergen purification methods successfully led to Ara h 2 purity, and the ability to standardize procedures to yield consistently pure samples. The purified allergen was chemically crosslinked with diketone derivatives selected for their abilities to react with specific amino acids accessible on the Ara h 2 protein. Chemically modified allergen samples were also evaluated using …

Development Of Novel Therapeutic Approaches: (I) Targeting Allergic Responses To Peanuts And (Ii) Inhibition Of Dpp-Iv Enzyme Involved In Diabetes, Savan V. Patel

Theses and Dissertations

There is an increase in prevalence of peanut allergy, especially in the western world. The only current treatment for peanut allergy is avoidance of peanut from diet and contact. Additionally, there is currently no specific vaccine that can be taken to decrease peanut allergies. The method of desensitizing a person allergic to peanut allergy is deemed unsafe as the smallest amount of peanut can trigger an anaphylaxis reaction. Thus, various allergoids were created by modifying major peanut protein allergen Ara h2 using various cross-linkers and modification agents in order to disrupt the binding surface epitopes of the antigen to antibody. …

From The Making To The Tuning To The Use Of Chlorins For Biomedical Applications, Junior Gonzales

Dissertations, Theses, and Capstone Projects

Chlorins are porphyrins missing a double bond. These pigments are optimal platforms for the development of novel dyes that display drug-like attributes such as photodynamic therapy (PDT) agents. More recently, it was demonstrated that chlorins can serve both as a PDT agent and as a modality for fluorescence or PET imaging. Thus, multifunctional chlorins eliminate the differences that may occur in specificity, uptake, and distribution between separate compounds or constructs for imaging and therapy. The overall goal of this dissertation is to take advantage of the reputed intrinsic attributes of chlorins as a viable tool in biomedical applications. In this …

Detection Of Cathinone And Mephedrone In Plasma By Lc-Ms/Ms Using Standard Addition Quantification Technique, Theron W. Ng-A-Qui

Student Theses

Designer drugs are structural analogs of Drug Enforcement Agency (DEA) Schedule I and II substances. They are synthesized to mimic the effects of illegal drugs of abuse and to bypass the provisions of drug regulations. Despite the increased availability of designer drugs, few studies have focused on specific analytical extraction techniques for their detection and quantification in biological samples. Solid phase extraction (SPE) is the most commonly used technique for sample preparation. The purpose of this study is to evaluate the extraction efficiency of the various SPE columns with different sorbent materials for two designer drugs, cathinone and mephedrone in …

Studies Directed Towards The Iridium Catalyzed Synthesis Of New Carbon-Nitrogen Bonds., Maria Lindsay

University of New Orleans Theses and Dissertations

Amines are ubiquitous in nature and serve a variety of functions in living organisms. Because of this fact amines are of great biological and pharmaceutical interest. The iridium catalyst (pentamethylcyclopentadienyl) iridium dichloride dimer ([Cp*IrCl₂]₂) has been used in a number of ways to synthesize new carbon-nitrogen bonds. These studies were directed toward the development of a method for the iridium catalyzed N-alkylation of alpha-amino acid esters as well as the development of a strategy for synthesis of the natural product 275A.

We have optimized a method for the N-alkylation for alpha-amino acid esters. Using this …

Design, Synthesis And Glioblastoma Activity Of 1,3-Diazinane Based Aryl Amides And Benzo Fused Heterocycles, Rebecca Hron

University of New Orleans Theses and Dissertations

The development of novel targeted therapeutics for the treatment of cancer remains difficult due to the complex nature of the disease itself as well as the challenges associated with the synthesis of these therapeutics. Impediments to the discovery of novel drug candidates include lack of available starting materials and access to well-developed syntheses which are both convenient and economically feasible. Semicarbazides, for instance, are a critical synthon for the manufacture of numerous biologically important molecules. Historically, convenient methods for the synthesis of semicarbazides and their derivatives did not exist. Recently, a facile and efficient method for the preparation of semicarbazides …

Understanding The Dynamic Process Of Dissolution Using In-Situ Ft-Ir Spectroscopy, Vrushali M. Bhawtankar

Seton Hall University Dissertations and Theses (ETDs)

Dissolution studies provide valuable and critical drug release information (in vitro) that are important for quality control drug development. Using in-situ FT-IR spectroscopy methods has been developed for analyzing and monitoring dissolutions of pharmaceutical APIs. The accuracy of this technique was found to be ± 3% relative to HPLC and UV/Vis Spectroscopy. A dynamic analysis of the dissolution and subsequent hydrolysis of aspirin has been determined by in-situ FT-IR. This technique allows real-time analysis of the behavior of aspirin under simulated physiological conditions (pH 1.2, 4.5, 6.8) as aspirin (1205 cm^-1) and salicylic acid (1388 cm^-1) …

Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia

Theses & Dissertations

The neurotensin receptor 1 (NTR1) is overexpressed in many cancers, due to its role as a growth pathway. These NTR1-positive cancers include pancreatic, colon, prostate and breast cancers. In the radiopharmaceutical field, the overexpression of NTR1 in cancer has prompted the development of NTR1-targeted diagnostics and therapeutics. The neurotensin (NT) peptide exhibits low nanomolar affinity for NTR1 and has been the paradigm for NTR1-targeted agents. Since the 1980’s, radiolabeled NT analogs have been developed and evaluated for targeting NTR1-positive cancers. Since native NT is rapidly degraded in vivo by a variety of peptidases, a tremendous amount of effort has been …

Molecular Basis Of Substrate Recognition In Bjai, An Ahl Synthase From Bradyrhizobium Japonicum, Nicole Cornell

Boise State University Theses and Dissertations

Resistance to antibiotics has become a major challenge in today’s society for treating bacterial infections. Inhibition of quorum sensing has a potential to be a non-antibiotic based therapeutic that could be used to fight these bacterial infections. Quorum sensing is a cell density dependent, intercellular communication mechanism that bacteria use to synchronize behavior such as virulence and resistance to antibiotics. If this switch from planktonic to communal behavior can be inhibited, the bacteria will be less virulent. One possible way to accomplish this is by inhibiting the enzymes that are responsible for making the quorum sensing signaling molecules in Gram-negative …

Synthesis And In-Vitro Cell Viability/Cytotoxicity Studies Of Novel Pyrrolobenzodiazepine Derivatives, John M. Jarrett

Undergraduate Honors Theses

Pyrrolobenzodiazepines (PBDs) are a group of naturally occurring compounds that were discovered in the cultures of Streptomyces in the 1960s. Some natural PBDs discovered in these cultures, such as anthramycin and sibiromycin, were shown to possess a broad spectrum of anti-tumor activity. Since cancer is still a leading cause of death globally, the development of novel anti-proliferative derivatives of PBDs is essential for human welfare worldwide. Further synthesis and structure-activity relationship (SAR) studies of the parent natural products and their tetracyclic analogs will lead to the discovery of drug candidates. In this work, thirteen PBD analogues were synthesized using no …

Cytotoxic And Antimicrobial Effects Of Silver-Containing Surfaces, Sarah Goderecci

Theses and Dissertations

This study examines applications of sputtered silver coatings as alternatives to traditional antibiotic treatments. Given the increase in reports of antibiotic-resistant bacteria, new treatments and coatings for in-dwelling medical devices such as catheters and orthopedic implants are necessary. Silver oxide films were deposited onto Ti surfaces to examine the efficacy of such coatings against a variety of bacterial species both in vitro and in vivo. Bacterial growth studies showed that coatings exhibited antimicrobial activity against a range of bacterial species acting either in a bacteriostatic or bactericidal mechanism, depending on the target. Limited toxicity to in vitro mammalian cells was …

Target Based Design And Synthesis Of Heterocycles In The Potential Treatment Of Cancer And Opportunistic Infection, Shruti Choudhary

Electronic Theses and Dissertations

Dose limiting toxicity and development of multidrug resistance by the tumors are the major limitations of current cancer chemotherapy. Microtubule targeting agents (MTAs) are a structurally diverse set of compounds that disrupt microtubule dynamics and exert their anticancer effect. Among the various classes of such agents, the colchicine site binding agents are particularly important as they circumvent the Pgp and β-III tubulin mediated clinical resistance. These resistance mechanisms, when manifested, are a major reason for the failure of clinically used agents such as taxanes and vinca alkaloids. A series of monocyclic pyrimidine analogs were designed and synthesized as colchicine site …

Nitric Oxide Release From Poly(Lactic-Co-Glycolic Acid) Nanoparticles And Titanium Alloy, Nina A. Reger

Electronic Theses and Dissertations

Current methods for the treatment of bacterial infection involve the use of systemic antibiotics, which are high concentrations of antibiotics delivered over a long period time. Unfortunately, the use of systemic antibiotics can cause harmful side effects to the patient and increases the possibility for antibiotic resistance. The delivery of antibiotics or alternative antimicrobial compounds, such as nitric oxide, directly to the site of infection would decrease the amount of antibiotic necessary to treat a bacterial infection.

Poly (lactic-co-glycolic acid)/polyvinyl alcohol nanoparticles and a titanium- aluminum-vanadium metal oxide alloy implant were surface functionalized to deliver nitric oxide. Polymer nanoparticles can …

Analysis Of Novel Cyanide Antidote Dimethyl Trisulfide For Pharmacokinetic Studies, And Sulfur Mustard Metabolites For Identification Of Biomarker Of Inhaled Dose, Erica Manandhar

Electronic Theses and Dissertations

Cyanide poisoning by accidental or intentional exposure poses a severe health risk. The current FDA approved antidotes for cyanide poisoning can be effective, but each suffers from specific major limitations. Dimethyl trisulfide (DMTS), a sulfur donor that detoxifies cyanide by converting it into thiocyanate, is a promising next generation cyanide antidote. Although a validated analytical method to analyze DMTS is not currently available from any matrix, one will be vital for the approval of DMTS as a therapeutic agent against cyanide poisoning. Hence, a stir bar sorptive extraction (SBSE) gas chromatography – mass spectrometry (GC-MS) method was developed and validated …

Literature Review On The Use Of Nucleic Acid-Based Logic Gates For The Detection Of Human Diseases, Enrique J. Blanco Martinez

Honors Undergraduate Theses

Conventional methods for diagnosis of human disease are, at times, limited in different regards including time requirement, either experimental or data processing, sensitivity, and selectivity. It is then that a Point of Care Criteria, which considers the true utility and usefulness of the device, is employed to propose new diagnostic devices capable of overcoming the aforementioned shortcomings of conventional tools. Nucleic acid, characterized for its predictable base-pairing nature, is considered to be a highly-selective, yet greatly modifiable device. Its behavior is then described through Boolean Logic, where “true” or “false” outputs are mathematically described as “1” and “0”, respectively. This …

Synthetic Methods For Ester Bond Formation And Conformational Analysis Of Ester-Containing Carbohydrates, Sven Hackbusch

University of the Pacific Theses and Dissertations

This dissertation encompasses work related to synthetic methods for the formation of ester linkages in organic compounds, as well as the investigation of the conformational influence of the ester functional group on the flexibility of inter-saccharide linkages, specifically, and the solution phase structure of ester-containing carbohydrate derivatives, in general.

Stereoselective reactions are an important part of the field of asymmetric synthesis and an understanding of their underlying mechanistic principles is essential for rational method development. Here, the exploration of a diastereoselective O-acylation reaction on a trans-2-substituted cyclohexanol scaffold is presented, along with possible reasons for the observed reversal of stereoselectivity …

Phage Display To Identify Functional Resistance Mutations To Rigosertib, Nedim Filipovic

CMC Senior Theses

In vitro protein selection has had major impacts in the field of protein engineering. Traditional screens assay individual proteins for specific function. Selection, however, analyzes a pool of mutants and yields the best variants. Phage display, a successful selection technique, also provides a reliable link between variant phenotype and genotype. It can also be coupled with high throughput sequencing to map protein mutations; potentially highlighting vital mutations in variants. We propose to apply this technique to cancer therapy. RAF, a serine/threonine kinase, is critical for cell regulation in mammals. RAF can be activated by oncogenic RAS, found in over 30% …

Development Of Diverse Size And Shape Rna Nanoparticles And Investigation Of Their Physicochemical Properties For Optimized Drug Delivery, Daniel L. Jasinski

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that holds great promise for advancing drug delivery and materials science. Recently, RNA nanoparticles have seen increased use as an in vivo delivery system. RNA was once thought to have little potential for in vivo use due to biological and thermodynamic stability issues. However, these issues have been solved by: (1) Finding of a thermodynamically stable three-way junction (3WJ) motif; (2) Chemical modifications to RNA confer enzymatic stability in vivo; and (3) the finding that RNA nanoparticles exhibit low immunogenicity in vivo.

In vivo biodistribution and pharmacokinetics are affected by the physicochemical …