Medicinal Chemistry and Pharmaceutics Commons^™

The Reaction Of Methionine With A Non-C2-Symmetrical Platinum (Ii) Diamine Compound, Nilesh Sahi

Mahurin Honors College Capstone Experience/Thesis Projects

The research that we have conducted has allowed us to discover that the amino acids, methionine (Met) and N-acetyl methionine (N-AcMet), will react in a 1:1 and 1:2 molar ratio with platinum complexes containing bulky diamine ligands. Previous research has allowed us to gain a plethora of information on the experimentation and results of specific bulky diamine ligands such as N,N,N',N'-tetramethylethylenediamine and N,N-diethylethylenediamine. In the current study, we have investigated the bulky diamine ligand of N,N-dimethylethylenediamine, or Me₂en. With our focus on the bulk of the Me₂en ligand, we have been able to synthesize a platinum …

Binding Efficacy Of Different Polyphenolic Phytochemicals With Β-Lactoglobulin And Human Serum Albumin: Implication For Therapeutics Against Neurodegenerative Diseases, Rene Duran^, Andres Ortiz^, Mahesh Narayan*, Vladik Kreinovich*

COURI Symposium Abstracts, Spring 2012

No abstract provided.

The Structural Requirements Of Histone Deacetylase (Hdac) Inhibitors: Suberoylanilide Hydroxamic Acid (Saha) Analogues Modified At C3, C6, And C7 Positions Enhance Selectivity, Sun Ea Choi

Wayne State University Dissertations

Histone deacetylase (HDAC) proteins are targets for drug design towards the treatment of cancers since overexpression of HDAC is linked to cancer. Several HDAC inhibitors, including the FDA approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat), have cleared clinical trials and emerged as anti-cancer drugs. However, SAHA inhibits all of the 11 metal ion-dependent HDAC proteins. Therefore, we synthesized several libraries of small molecule HDAC inhibitors based on SAHA to help understand the structural requirements of inhibitory potency and isoform selectivity.

In previous work, SAHA analogues functionalized at the C2 position (C2-SAHA analogues) near the metal binding hydroxamic acid displayed decreased …

Novel Inhibitors Of The Bacterial De Novo Purine Biosynthesis Enzymes, N5-Carboxyaminoimidazole Ribonucleotide Synthetase And Mutase, Maria V. Fawaz

Wayne State University Theses

Antibiotic resistance has seen a significant increase during the past decade. The increasing frequency of the drug-resistant bacterial infections has amplified the need for novel antimicrobial agents. De novo purine biosynthesis is one area that has great potential for antibacterial drug development because this pathway is different in microorganisms versus humans. The difference in the pathway is centered on the synthesis and utilization of the purine intermediate N⁵-carboxy-5-aminoimidazole ribonucleotide (N⁵-CAIR). Previous studies have shown that N⁵-CAIR is a key intermediate in purine biosynthesis in bacteria, yeast and fungi, but not in humans. N^{5 …}

Modulating The Pharmacokinetics Of Bioflavonoids, Adam John Smith

USF Tampa Graduate Theses and Dissertations

One of the largest obstacles in drug development is to overcome solubility and bioavailability problems. Preformulation strategies such as nanoparticle formation are often employed but sometimes create new issues and are limited in their effectiveness and applications. Since the majority of drugs are marketed and sold as solid forms, drug delivery systems are not always desirable. This is where solid-state chemistry becomes important. Traditional solid-state chemistry approaches are often successful but are sometimes too restrictive and cannot be applied to certain compounds. Cocrystals have emerged as an alternative solid-state technique that can be applied to a broad range of compounds. …

Investigation Of The Absorptive Potential Of Polymeric Nanoparticles Across The Lungs And Their Development For Efficient Systemic Delivery Following Pulmonary Administration, Abdul Khader Mohammad

Wayne State University Dissertations

The lungs are an attractive route for drug delivery due to their high epithelial surface area available for absorption, a thin epithelium and extensive vasculature to name a few. Accordingly, a vast number of small molecule drugs, peptides, and proteins have been used to investigate their translocation across the lungs with many of the tested candidates showing excellent pharmacokinetics following pulmonary administration. Findings from all these studies over the years have strongly established the lungs as a route for drug delivery of small molecules and proteins. Nanoparticles on the other hand have gained increasing interest in drug delivery due to …

Multifunctional Bioreducible Nanoparticles For Gene Therapy, Jing Li

Wayne State University Dissertations

Gene therapy is a promising therapeutic strategy to treat diseases caused by single or multiple gene mutations. Non-viral gene delivery vectors exhibit many advantages over viral vectors, including enhanced safety, versatility in choosing different types of therapeutic nucleic acids, and ease of formulation. However, low transgene efficiency and lack of targeting ability remain major challenges. Bioreducible polyplexes (polyelectrolyte complexes of disulfide-containing polycations and nucleic acids) utilize the redox potential gradient existing between extracellular space and intracellular environment as a physiological stimulus to enhance delivery of therapeutic nucleic acids to the subcellular space. Bioreducible containing polyplexes undergo intracellular reduction mediated GSH, …

Comparison Of Subcellular Responses For The Evaluation And Prediction Of The Chemotherapeutic Response To Cisplatin In Lung Adenocarcinoma Using Raman Spectroscopy, Haq Nawaz, Franck Bonnier, Aidan Meade, Fiona Lyng, Hugh Byrne

Articles

Confocal Raman Micro spectroscopy (CRM) is employed to examine the chemical and physiological effects of anticancer agents, using cisplatin and A549 adenocarcinoma cells as a model compound and test system respectively. Spectral responses of the membrane and cytoplasm of the cell are analysed independently and the results are compared to previously reported spectroscopic studies of the nucleus. Moreover, Raman spectra from the proteins extracted from the control and exposed samples are acquired and analysed to confirm the origin of the molecular changes of the cell membrane and cytoplasm of the A549 cells. Multivariate data analysis techniques including Principal Component Analysis …

Novel Inhibitors Of Lysine Specific Demethylase 1 As Epigenetic Modulators, Michael Crowley

Wayne State University Theses

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 over expression is thought to contribute to the development of cancer. We recently reported a series of (bis)guanidines and (bis)biguanides that are potent inhibitors of LSD1, and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a new series of isosteres that are also potent inhibitors of LSD1. These compounds induce increases in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target …

The Impact Of Tricaine Methanesulfonate, 2-Phenoxyethanol, And Carvone-Methyl Salicylate On The Innate Immune Response Of Zebrafish (Danio Rerio), Charles R. Wulff

Honors Theses

Anesthesia plays a vital role in the maintenance of aquaculture species, where it is used to minimize stress during complex handling tasks such as transport, assessment, and harvesting. However, anesthetics have been shown to suppress the innate immune response, which could impact immunity and increase risk of infection. Tricaine methanesulfonate (MS-222) and 2-Phenoxyethanol (2-PE) represent two of the most commonly used anesthetics in aquaculture, with R-(+)-carvone, in the form of carvone-methyl salicylate (CMS) has recently been proposed as an alternative anesthetic for food fish. These three anesthetics were used to assess the influence of anesthetics on the immune system of …

Synthesis, Evaluation And Structural Studies Of Antiproliferative Tubulin-Targeting Azetidin-2-Ones, Niamh O'Boyle, Lisa M. Greene, Orla Bergin, Jean-Baptiste Fichet, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

A series of azetidin-2-ones substituted at positions 2, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerization that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the …

Small Gtp-Binding Proteins In Insulin Secretion, Bhavaani Jayaram

Wayne State University Dissertations

Type 2 diabetes mellitus is marked by a substantial beta-cell failure which is characterized by defective insulin secretion and resistance to insulin. Understanding the molecular events leading to Glucose-stimulated insulin secretion [GSIS] might serve as therapeutic potential towards diabetes. GSIS involves interplay between small G-proteins and their regulatory factors. Herein, I tested the hypothesis that Arf nucleotide binding site opener [ARNO], a guanine nucleotide exchange factor [GEF] for the small G-protein Arf6, mediates the activation of Arf6, and that ARNO/Arf6 signaling axis, in turn, controls the activation of downstream effectors. Salient features of my study are: [i] ARNO/Arf6 is expressed …

Mechanisms Of Regulation Of Islet Function By Nadph Oxidase, Ismail Syed

Wayne State University Dissertations

Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS …

Synthesis, Biochemical And Molecular Modelling Studies Of Antiproliferative Azetidinones Causing Microtubule Disruption And Mitotic Catastrophe, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Niall O. Keely, Andrew Js Knox, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC₅₀ value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for …

Lead Identification Of Β-Lactam And Related Imine Inhibitors Of The Molecular Caperone Heat Shock Protein 90, Niamh O'Boyle, Andrew Js Knox, Trevor P. Price, D. Clive Williams, Daniela M. Zisterer, David G. Lloyd, Mary J. Meegan

Articles

Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the identification of inhibitors based on β-lactam and imine templates. β-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC₅₀ values of 5.6 μM, 14.5 μM and 22.1 μM respectively. The binding affinity displayed …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asiaderived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the …

Anticancer And Antifungal Activity Of Copper(Ii) Complexes Of Quinolin-2(1h)-One-Derived Schiff Bases, Bernadette S. Creaven, Brian Duff, Denise A. Egan, Kevin Kavanagh, Georgina Rosair, Venkat Reddy Thangella, Maureen Walsh

Articles

The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2–14). The copper(II) complexes (2a–14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, ¹H and ¹³C NMR, AAS, UV–Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate …

Sesquiterpenes And Dimeric Sesquiterpenoids From Sarcandra Glabra, Xiu-Feng He, Sheng Yin, Yin-Chun Ji, Zu-Shang Su, Mei-Yu Geng, Jian-Min Yue

Faculty Publications

Two new sesquiterpenes, sarcandralactones A (1) and B (2), and five new dimeric sesquiterpenoids, sarcandrolides A-E (3-7), along with 10 known compounds were isolated from the whole plants of Sarcandra glabra. Their structures were elucidated on the basis of spectroscopic analysis. Some of the new isolates exhibit significant cytotoxicities when tested against a small panel of tumor cell lines.

Special 301 And Access To Medicine In The Obama Administration, Sean Flynn

Scholarly Articles in Law Reviews & Journals

I. Introduction

This article examines the history and current use of the Special 301 program to restrict access to generic medicines in developing countries, specifically the 2009 and 2010 reports released under the Obama Administration. The news for access to medicines advocates is not good overall. Both reports continue the previous Administration’s policies of using Special 301 to promote Trade-Related Aspects of Intellectual Property Rights (“TRIPS”) policies (“TRIPS-plus”) endangering access to medicines for millions of people worldwide. These policies violate not only the Obama Administration’s pledges to promote access to affordable medications in developing countries, but also U.S. commitments under …

Antidepressant Stimulation Of Cdp-Diacylglycerol Synthesis Does Not Require Monoamine Reuptake Inhibition, Ashiwel S. Undieh, Marwa A. Aboukhatwa

Publications and Research

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of …

Synthesis And Evaluation Of Azetidinone Analogues Of Combretastatin A-4 As Tubulin Targeting Agents, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Orla Bergin, Seema M. Nathwani, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41 and …

Copper(Ii) Complexes Of Coumarin-Derived Schiff Bases And Their Anti-Candida Activity, Bernadette S. Creaven, Michael Devereux, Dariusz Karcz, Andrew Kellett, Malachy Mccann, Andy Noble, Maureen Walsh

Articles

The condensation of 7-amino-4-methyl-coumarin (1) with a number of substituted salicylaldehydes yielded a series of Schiff bases (2a–2k) in good yields. Subsequent reaction of these ligands with copper( II) acetate yielded Cu(II) complexes (3a–3k) and some were characterised using X-ray crystallography. All of the free ligands and their metal complexes were tested for their anti-Candida activity.

Apoptotic And Chemotherapeutic Properties Of Iron (Iii)-Salophene In An Ovarian Cancer Animal Model, Thilo S. Lange, Carolyn Mccourt, Rakesh K. Singh, Kyu Kwang Kim, Ajay P. Singh, Brian S. Luisi, Onur Alptürk, Robert M. Strongin, Laurent Brard

Chemistry Faculty Publications and Presentations

The cytotoxicity of organometallic compounds iron(III)-, cobalt(III)-, manganese(II)-, and copper(II)-salophene (-SP) on platinum-resistant ovarian cancer cell lines was compared. Fe-SP displayed selective cytotoxicity (IC(50) at ~1 muM) against SKOV-3 and OVCAR-3 cell lines while Co-SP caused cytotoxic effects only at higher concentrations (IC(50) at 60 muM) and Cu-SP effects were negligible. High cytotoxicity of Mn-SP (30-60 muM) appeared to be nonspecific because the Mn-chloride salt reduced cell viability similarly. The effect of Fe-SP at 1 muM proved to be ovarian cancer cell selective when compared to a panel of cell lines derived from different tumors. The first irreversible step in …

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Collected Faculty Scholarship

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

Genome-Wide Compensatory Changes Accompany Drug Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Collected Faculty Scholarship

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …

Iron(Iii)-Salophene: An Organometallic Compound With Selective Cytotoxic And Anti-Proliferative Properties In Platinum-Resistant Ovarian Cancer Cells, Thilo S. Lange, Kyu Kwang Kim, Rakesh K. Singh, Robert M. Strongin, Carolyn Mccourt, Laurent Brard

Chemistry Faculty Publications and Presentations

Background: In this pioneer study to the biological activity of organometallic compound Iron(III)-salophene (Fe-SP) the specific effects of Fe-SP on viability, morphology, proliferation, and cell-cycle progression on platinum-resistant ovariancancer cell lines were investigated.

Methodology/Principal Findings: Fe-SP displayed selective cytotoxicity against SKOV-3 and OVCAR-3 (ovarian epithelial adenocarcinoma) cell lines at concentrations between 100 nM and 1 μM, while the viability of HeLa cells (epithelial cervix adenocarcinoma) or primary lung or skin fibroblasts was not affected. SKOV-3 cells in contrast to fibroblasts after treatment with Fe-SP revealed apparent hallmarks of apoptosis including densely stained nuclear granular bodies within fragmented nuclei, highly condensed …

Respiratory Effects Of 1-Propylxanthine On Neonatal Rats, Amanda Hance

Student Honors Theses

Neonatal apnea is commonly treated by methylxanthines like caffeine or theophylline, but these drugs have the potential to create serious side effects. As an alternative, a new xanthine analog, 1-propylxanthine (1-PX), was recently synthesized at Eastern Illinois University. The respiratory effects of 1-PX were investigated in 4- to 7-day-old rats to determine if 1-PX could be a respiratory stimulant. Each rat was placed in a heated body plethysmograph, and its respiratory rate and volume were measured using a flow transducer, pneumotachograph, and Power Lab data acquisition system. After a 10-min control period, the rat was given a s.c. dose of …

The Evaluation Of Midazolam On Head Injured Patients In The Prehospital Setting, Dragana Klinac

Theses: Doctorates and Masters

Midazolam (Hypnovel ®) is the only sedating agent used by paramedics at St John Ambulance Service W.A. in the management of many conditions including seizure activities, antisocial or uncontrollable behaviours, back pain incidents and head injuries. Midazolam, with a rapid absorption, fast onset of action and short duration on neurological activity, has been accepted as a safe and effective agent in prehospital treatment since the late-1990s. Often, if a patient is not complying with treatment or is uncontrollable or aggressive, paramedics are required to sedate the individual. This study primarily examines the use of midazolam for the sedation of unmanageable …

La Flore Qui A Faim : Une Enquête Chimique, Biologique Et Culturelle De La Dimorphisme Rouge/Verte Et Les Applications Médicinales De Nepenthes Madagascariensis, Keirnan Willett

Independent Study Project (ISP) Collection

Le Nepenthes madagascariensis est une plante carnivore endémique du côté sud-est de Madagascar qui attirent la proie arthropode (insectes, araignées etc.) en employant les bouts de feuilles convertis en forme des pichets ou urnes. Après d’être attiré par le suc au bord de l’urne, les insectes devint désorientés, perdent la traction et se coulent dans le liquide riche en enzymes digestifs au dessous (14). Les substances nutritives des cadavres sont absorbées par la plante en compensant pour la lacune d’azote dans le sol. Les couvercles des urnes expriment une couleur rouge ou verte. Notre étude examine les différences chimiques et …

Bioprospecting, Philip A. Reed

STEMPS Faculty Publications

The article discusses that the product applications of bioprospecting are almost limitless. This area of biotechnology has been labeled bioprospecting, and it is a practice that is creating worldwide controversy. Defined simply, bioprospecting is "scientific research that looks for a useful application, process, or product in nature." However, as with most biotechnologies, the definition does not address the complexities of bioprospecting. Archeologists are finding that some biotechnologies, such as the use of herbs for medicine and the use of fermentation and yeast in food products, date back 5,000 to 10,000 years (De Miranda, 2004). The four main categories of biotechnologies …