Medicinal-Pharmaceutical Chemistry Commons^™

Fluoroethoxy-1,4-Diphenethylpiperidine And Piperazine Derivatives: Potent And Selective Inhibitors Of [3H]Dopamine Uptake At The Vesicular Monoamine Transporter-2, Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks

Pharmaceutical Sciences Faculty Publications

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [³H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [³H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [³H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [³H]DA uptake at VMAT2, with Ki values in the nanomolar range (K_i = 0.014–0.073 μM). Compound 15d exhibited the highest affinity (K_i = 0.014 μM) at VMAT2, and had 160-, 5-, …

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 …

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 …

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. …

Toxicant Formation In Dabbing: The Terpene Story, Jiries Meehan-Attrash, Wentai Luo, Robert M. Strongin

Chemistry Faculty Publications and Presentations

Inhalable, noncombustible cannabis products are playing a central role in the expansion of the medical and recreational use of cannabis. In particular, the practice of “dabbing” with butane hash oil has emerged with great popularity in states that have legalized cannabis. Despite their growing popularity, the degradation product profiles of these new products have not been extensively investigated. The study herein focuses on the chemistry of myrcene and other common terpenes found in cannabis extracts. Methacrolein, benzene, and several other products of concern to human health were formed under the conditions that simulated realworld dabbing. The terpene degradation products observed …

Design, Synthesis, And Biological Activity Of 5'-Phenyl-1,2,5,6-Tetrahydro-3,3'-Bipyridine Analogues As Potential Antagonists Of Nicotinic Acetylcholine Receptors, Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D Showalter, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (K_i = 123 nM) …

Dietary Guidelines And Its Implications For Coconut Oil, Fabian M. Dayrit

Chemistry Faculty Publications

The dietary advice that is generally followed nationally and internationally closely follows the Dietary Guidelines for Americans which was first published in 1980 and which has been through eight editions. All of the editions of the Dietary Guidelines recommend a diet that is low in fat, and most editions recommend the replacement of saturated fat with polyunsaturated fat. This recommendation is based on the saturated fat-cholesterol-heart disease hypothesis that was first proposed by Ancel Keys in the 1950s. Coconut oil was labeled as unhealthy because of its high saturated fat composition. However, this label is unwarranted. Re-analysis of the work …

Synthesis And Antitumor Activity Of N-Triazol-5-Yl-Oxazolidin-4-One Derivatives., R. Luo, S. Guo, Shilong Zheng, Guangdi Wang, X. Bao, L. He

Faculty and Staff Publications

Fifteen novel N-triazol-5-yl-oxazolidin-4-ones were synthesized through a few of steps from the benzaldehydes. It was found that N-iodosuccinimide (NIS) can promote intramolecular amination reaction which is the key step of the syntheses, which will be used as new method for the intramolecular formation of nitrogen-containing heterocycles. Part of the compounds were evaluated for their anticancer activity. Among them, compounds 6a, 6b and 6c showed moderate antiprolifiration activity toward human breast cancer cells MDA-MB-231 cell lines, while the mild activity of 6a, 6b and 6d against human cervical cancer HeLa cell lines was confirmed in vitro assay.

Nonlinear Oscillatory Dynamics Of The Hardening Of Calcium Phosphate Bone Cements, Vuk Uskoković, Julietta V. Rau

Pharmacy Faculty Articles and Research

Here we report on the nonlinear, oscillatory dynamics detected in the evolution of phase composition during the setting of different calcium phosphate cements, two of which evolved toward brushite and one toward hydroxyapatite as the final product. Whereas both brushite-forming cements contained iondoped b-tricalcium phosphate as the initial phase, the zinc-containing one yielded scholzite as an additional phase during setting and the oscillations between these two products were pronounced throughout the entire 80 h setting period, long after the hardening processes was over from the mechanical standpoint. Oscillations in the copper-containing system involved the amount of brushite as the main …

Selective Inhibitors Of Human Mpges-1 From Structure-Based Computational Screening, Ziyuan Zhou, Yaxia Yuan, Shuo Zhou, Kai Ding, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors with mPGES-1 provide …

Traceable Peo-Poly(Ester) Micelles For Breast Cancer Targeting: The Effect Of Core Structure And Targeting Peptide On Micellar Tumor Accumulation, Shyam M. Garg, Igor M. Paiva, Mohammad R. Vakili, Rania Soudy, Kate Agopsowicz, Amir H. Soleimani, Mary Hitt, Kamaljit Kaur, Afsaneh Lavasanifar

Pharmacy Faculty Articles and Research

Traceable poly(ethylene oxide)-poly(ester) micelles were developed through chemical conjugation of a near-infrared (NIR) dye to the poly(ester) end by click chemistry. This strategy was tried for micelles with poly(ε-caprolactone) (PCL) or poly(α-benzyl carboxylate-ε-caprolactone) (PBCL) cores. The surface of both micelles was also modified with the breast cancer targeting peptide, P18-4. The results showed the positive contribution of PBCL over PCL core on micellar thermodynamic and kinetic stability as well as accumulation in primary orthotopic MDA-MB-231 tumors within 4–96 h following intravenous administration in mice. This was in contrast to in vitro studies where better uptake of PEO-PCL versus PEO-PBCL micelles …

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 …

Development Of Entrapment Columns For The Study Of Affinity Based Analysis Of Drug–Protein Interactions, Shiden T. Azaria

Department of Chemistry: Dissertations, Theses, and Student Research

High-performance affinity chromatography (HPAC) is a type of liquid chromatography in which solutes are separated based on their binding to a stationary phase that is a biologically-related agent. Because of the strong and selective nature of many biological interactions, this method has already become a powerful technique for the purification and analysis of solutes that are complementary to the immobilized binding agent. Human serum albumin (HSA), the most abundant protein in the blood with concentrations of 35-50 mg/mL in serum, has interactions with many drugs, which can affect the absorption, distribution, metabolism and excretion of such agents.

The overall goal …

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 …

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 …

Antifungal Potential Of Copper(Ii), Manganese(Ii) And Silver(I) 1,10-Phenanthroline Chelates Against Multidrug-Resistant Fungal Species Forming The Candida Haemulonii Complex: Impact On The Planktonic And Biofilm Lifestyles, Rafael M. Gandra, Pauraic Mc Carron, Mariana F. Fernandes, Lívia S. Ramos, Thaís P. Mello, Ana Carolina Aor, Marta H. Branquinha, Malachy Mccann, Michael Devereux, André L. S. Santos

Articles

Candida haemulonii, Candida haemulonii var. vulnera and Candida duobushaemulonii, which form the C. haemulonii complex, are emerging etiologic agents of fungal infections known to be resistant to the most commonly used antifungals. The well-established anti-Candida potential ofmetal complexes containing 1,10-phenanthroline (phen) ligands encouraged us to evaluate different copper(II), manganese(II), and silver(I) phen chelates for their ability to inhibit planktonic growth and biofilm of C. haemulonii species complex. Two novel coordination complexes, {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n and [Ag2(3,6,9-tdda)(phen)4].EtOH (3,6,9-tddaH2 = 3,6,9-trioxaundecanedioic acid), were synthesized in a similar fashion to the other, previously documented, sixteen copper(II), manganese(II), and silver(I) chelates employed herein. Three isolates of …

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 …

Formulation, Characterisation And Stability Assessment Of A Food Derived 1 Tripeptide, Leucine-Lysine-Proline Loaded Chitosan Nanoparticles, Minna Khalid Danish, Giuliana Vozza, Hugh Byrne, Jesus Maria Frias, Sinead Ryan

Articles

The chicken or fish derived tripeptide, Leucine-Lysine-Proline (LKP), inhibits the Angiotensin Converting Enzyme and may be used as an alternative treatment for pre-hypertension. However, it has low permeation across the small intestine. The formulation of LKP into a nanoparticle (NP) has the potential to address this issue. LKP-loaded NPs were produced using an ionotropic gelation technique, using chitosan (CL113). Following optimisation of unloaded NPs, a mixture amount design was constructed using variable concentration of CL113 and tripolyphosphate at a fixed LKP concentration. Resultant particle sizes ranged from 120-271 nm, zeta potential values from 29-37 mV and polydispersity values from 0.3-0.6. …

Cytotoxicity Of Platinum Anticancer Drugs In Mammalian Cell Lines Of Metastatic Cancer, Hosannah Evie

Mahurin Honors College Capstone Experience/Thesis Projects

With the invention of advanced technology, focus has been put on understanding and looking for potential cures for many diseases, one of which is cancer. The difference in the leaving and non-leaving ligands of the FDA approved cancer drugs contributes to the differential cell specific cytotoxic effects. These drugs such as oxaliplatin approved for colorectal cancer, cisplatin approved for testicular cancer, and their analogs were used to treat different cancer cell lines in an MTT assay. This project aims to determine how changing the molecular shape of these compounds affects their uptake and toxicity into different cell lines. The assay …

Inhibiting Translesion Dna Synthesis As An Approach To Combat Drug Resistance To Dna Damaging Agents, Jung-Suk Choi, Seol Kim, Edward Motea, Anthony J. Berdis

Chemistry Faculty Publications

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced …

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.

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 …

Copalic Acid Analogs Down-Regulate Androgen Receptor And Inhibit Small Chaperone Protein, Nethrie D. Idippily, Qiaoyun Zheng, Chunfang Gan, Aicha Quamine, Morgan M. Ashcraft, Bo Zhong, Bin Su Ph.D.

Chemistry Faculty Publications

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive …

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 …

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 …