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 …

Folding Of Bovine Pancreatic Trypsin Inhibitor (Bpti) Is Faster Using Aromatic Thiols And Their Corresponding Disulfides, Ram Prasad Marahatta

FIU Electronic Theses and Dissertations

Improvement in the in vitro oxidative folding of disulfide-containing proteins, such as extracellular and pharmaceutically important proteins, is required. Traditional folding methods using small molecule aliphatic thiol and disulfide, such as glutathione (GSH) and glutathione disulfide (GSSG) are slow and low yielding. Small molecule aromatic thiols and disulfides show great potentiality because aromatic thiols have low pKa values, close to the thiol pKa of protein disulfide isomerase (PDI), higher nucleophilicity and good leaving group ability. Our studies showed that thiols with a positively charged group, quaternary ammonium salts (QAS), are better than thiols with negatively charged groups such as phosphonic …

Progress Toward Phidianidine Analogues Containing A 1,2,3-Triazole Ring, David Laws Iii, Dillon King, Bryan H. Wakefield

Journal of the South Carolina Academy of Science

Phidianidines are a class of compound that has been extracted from the sea mollusk Phidianis militaris. These compounds have been shown to exhibit a variety of useful properties such as antihistamine effects, anti-cancer activity, agonism of the µ-opioid receptor and neuroprotection. The biological activities are thought to be caused by the 1,2,4- oxadiazole ring found within the molecule. The goal of this project is to synthesize analogues of phidianidine that contain a 1,2,3-triazole instead of the 1,2,4 oxadiazole ring using a method that will allow for other regions of the molecule to be changed. This will help to elucidate …

Ensemble-Based Modeling And Rigidity Decomposition Of Allosteric Interaction Networks And Communication Pathways In Cyclin-Dependent Kinases: Differentiating Kinase Clients Of The Hsp90-Cdc37 Chaperone, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The overarching goal of delineating molecular principles underlying differentiation of protein kinase clients and chaperone-based modulation of kinase activity is fundamental to understanding activity of many oncogenic kinases that require chaperoning of Hsp70 and Hsp90 systems to attain a functionally competent active form. Despite structural similarities and common activation mechanisms shared by cyclin-dependent kinase (CDK) proteins, members of this family can exhibit vastly different chaperone preferences. The molecular determinants underlying chaperone dependencies of protein kinases are not fully understood as structurally similar kinases may often elicit distinct regulatory responses to the chaperone. The regulatory divergences observed for members of CDK …

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 …

Progress Toward The Development Of A "Catch/Release" Strategy For Isolating Salvinorin A, From Plant Materails Including Microwave Promotion, Douglas Armstrong, Logan Smith

Faculty Scholarship – Chemistry

We are investigating using the Diels-Alder and retro-Diels-Alder reactions as a potential “catch/release” strategy for isolating Salvinorin A from plant samples (Salvia divinorum), hopefully to improve the current method, which is very long and laborious. Salvinorin A has analgesic activity by activating the kappa opioid receptor, not the mu receptor, and thus it has potential for being developed into a non-addicting analgesic.

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 …

Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions ofmenthol. There has been new evidence demonstrating thatmenthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at …

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 …

Solid-Phase Peptide Synthesis Of Analogues Of The N-Terminus A-Ring Fragment Of The Lantibiotic Nisin: Replacements For The Dehydroalanine (Dha) Residue At Position 5 And The First Incorporation Of A Thioamide Residue, Kim Manzor, Keith Ó Proinsias, Fintan Kelleher

Articles

A number of A-ring analogues of the lantibiotic nisin, containing replacements for the Dha at position 5, have been successfully prepared by solid-phase peptide synthesis. The Dha replacements include glycine, alanine, phenylalanine, serine and 1-aminocyclopropyl carboxylic acid (ACCa). The incorporation of a thioamide-isoleucine residue at position 4 is also described and is the first report of the preparation of a lantibiotic ring fragment containing a thioamide link.

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 …

Conformational Studies Of Gram-Negative Bacterial Quorum Sensing 3-Oxo N-Acyl Homoserine Lactone Molecules, Darren Crowe, Alan Nicholson, Adrienne Fleming, Ed Carey, Goar Sanchez-Sanz, Fintan Kelleher

Articles

In their ¹H NMR spectra in CDCl₃ 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide N-H proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the N-H to the 3-oxo group. The ¹H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1-4.5% in CDCl₃ and 6.5-7.2% in CD₃CN. 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 …

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 …

Docking Studies Of Isoform-Selectivity Of Phosphatidylinositol 3-Kinase (Pi3k) Inhibitors, Kaitlin Goettsch

UNO Student Research and Creative Activity Fair

Phosphatidylinositol 3-kinases (PI3Ks) and their related pathways are reputed targets for drug-based anticancer therapies. Mutations in PI3K genes, expression, and pathways are frequent among multiple cancer types. Four isoforms of PI3Ks exist: α, β, γ, & δ and studies have identified several ligands for each isoform which are capable of serving as inhibitory therapeutic compounds. However, the biochemical efficacy of these molecules varies and the isoform selectivity is not well understood. In this study, we applied in silico docking methods and free energy calculation methods to estimate the binding of reported PI3K ligands against 5 PI3K structures: PI3Kα (PBD ID: …

Ligands Of Therapeutic Utility For The Liver X Receptors., Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar

Faculty and Staff Publications

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. …

Synthesis And Biological Activity Of Novel Tu100 Derivatives, Oladotun J. Alao

Electronic Theses and Dissertations

In an attempt to create more effective chemotherapeutic compounds, the naphthoquinone adduct, 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta [1,2 b]naphthalen-5,12-imine (hereafter called TU100) was synthesized. Inspired by its unique and novel mechanism of action, a series of structural derivatives were synthesized to explore structure-activity relationships. The analogues exhibited different cytotoxicity profiles, revealing the indicated regions are involved in cell death induction. Furthermore, the analogues had dramatically different effects on cellular ATP production, suggesting different molecular targets. Synthesis, biological activity, and SAR study of these analogues will be revealed.

Synthesis Of Multifunctional Polyacrylates And A Binding Group To Hemoglobin For The Treatment Of Traumatic Brain Injuries, Marina Michaud

Honors College Theses

Hemoglobin based oxygen carriers (HBOCs) hold promise as an effective emergency treatment of severe traumatic brain injuries (TBI). In the latest generation of HBOCs, polynitroxyl-pegylated hemoglobin (PNPH), cell-free hemoglobin is modified with TEMPO and PEG which reduce the toxicities associated with earlier generations of HBOCs. In our efforts to optimize the economic and therapeutic impacts of PNPH’s we have synthesized polydimethylaminoethyl methacrylate (poly-DMAEMA) under controlled living conditions via reverse addition-fragmentation chain transfer (RAFT) polymerization. The poly-DMAEMA was then successfully functionalized via quaternization of its NMe₂ groups using chloroacetate derivatives of the TEMPO and PEG. This process was quantitative and …