Pharmacology, Toxicology and Environmental Health Commons^™

Novel Cis-Restricted Β-Lactam Combretastatin A-4 Analogues Display Anti-Vascular And Anti-Metastatic Properties In Vitro, Seema M. Nathwani, Lisa M. Greene, Linda Hughes, Miriam Carr, Niamh O'Boyle, Susan Mcdonnell, Mary J. Meegan, Daniela M. Zisterer

Articles

No abstract provided.

Progress Towards Development Of Multifunctional, Dopamine D2/D3 Receptor Agonists As Symptomatic And Disease-Modifying Therapeutic Agents For Parkinson's Disease, Mark Andrew Johnson

Wayne State University Dissertations

Parkinson¡¯s disease (PD) is a progressive, neurodegenerative disorder that arises primarily through the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in a diminished level of the neurotransmitter dopamine in the nigrostriatal pathway and ensuing loss of motor function. Common symptoms of PD include resting tremor, muscular rigidity, bradykinesia (slowness and decreased amplitude of movement), along with postural instability and cognitive psychiatric complications. PD affects 1% of the population ¡Ý 65 and is the second most prevalent neurodegenerative disorder next to Alzheimer¡¯s disease (AD). Although the etiology of PD is not yet clear and may be …

Progress Towards Understanding Of Mechanisms Of Action Of Potent Multifunctional Disease Modifying Therapeutics For Parkinson's Disease & Investigating The Methamphetamine-Induced Striatal Microglia Activation., Mrudang M. Shah

Wayne State University Dissertations

PROGRESS TOWARDS UNDERSTANDING OF MECHANISMS OF ACTION OF POTENT MULTIFUNCTIONAL DISEASE MODIFYING

THERAPEUTICS FOR PARKINSON'S DISEASE.

by

MRUDANG MANOJKUMAR SHAH

December 2013

Advisor: Dr. Aloke Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Our long term goal is to design and develop potent multifunctional disease modifying therapeutics for Parkinson's disease. The objective of my dissertation was to understand the mechanisms of action of some potent small molecules (synthesized in our lab) as a disease modifying Parkinson's disease therapeutic. The objective was achieved by pursuing the following two specific aims:

1. Investigating anti-oxidant and neuroprotective effects of a lead molecule (D-512) …

Design, Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Multifunctional Neuroprotective Drugs For The Treatment Of Parkinson's Disease: An Effort Towards The Improvement Of In Vivo Efficacy And Modulation Of Alpha Synuclein Aggregation Property Of The Neuroprotective Parent, Gyan Prakash Modi

Wayne State University Dissertations

DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR MODELING STUDIES OF NOVEL MULTIFUNCTIONAL NEUROPROTECTIVE DRUGS FOR THE TREATMENT OF PARKINSON'S DISEASE: AN EFFORT TOWARDS THE IMPROVEMENT OF IN VIVO EFFICACY AND MODULATION OF ALPHA SYNUCLEIN AGGREGATION PROPERTY OF THE NEUROPROTECTIVE PARENT MOLECULE (D-264)

by

GYAN PRAKASH MODI

May 2014

Advisor: Dr. Aloke K. Dutta

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Parkinson's disease (PD) is a progressive age-related neurodegenerative disorder of the central nervous system that is characterized by gradual loss of dopaminergic neurons in the substantia nigra region of the brain. The research from the past two decades in PD area …

Cure From The Cave: Volcanic Cave Actinomycetes And Their Potential In Drug Discovery, Naowarat (Ann) Cheeptham Dr., Tara Sadoway, Devon Rule, Kent Watson, Paul Moote, Laiel C. Soliman, Nicholas Azad, Kingsley Donkor, Derrick Horne

International Journal of Speleology

Volcanic caves have been little studied for their potential as sources of novel microbial species and bioactive compounds with new scaffolds. We present the first study of volcanic cave microbiology from Canada and suggest that this habitat has great potential for the isolation of novel bioactive substances. Sample locations were plot ted on a contour map that was compiled in ArcView 3.2. Over 400 bacterial isolates were obtained from the Helmcken Falls cave in Wells Gray Provincial Park, British Columbia. From our preliminary screen, of 400 isolates tested, 1% showed activity against extended spectrum ß-lactamase E. coli, 1.75% against Escherichia …

Synthesis And Biochemical Activities Of Antiproliferative Amino Acid And Phosphate Derivatives Of Microtubule-Disrupting Beta-Lactam Combretastatins, Niamh M. O'Boyle, Lisa M. Greene, Niall O. Keely, Shu Wang, Tadhg S. Cotter, Daniela M. Zisterer, Mary J. Meegan

Articles

The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of …

Formulation Devlopment Of Mesoporous Silica Nanoparticles As An Injectable Delivery System, Amit S. Wani

Wayne State University Dissertations

Our long term goal is to develop a versatile and robust injectable carrier based on Mesoporous Silica Nanoparticles (MSN) for drug/drug combination therapies. The objective of my dissertation was to optimize surface functionality, particle shape and methods of colloidal stabilization of mesoporous silica by PEG for delivery of drug/drug combinations. This was achieved by pursuing the following three aims:

1. Optimize surface functionality of MSN for high drug loading and controlled release

2. Investigate the effect of particle shape and PEGylation on drug delivery in hypoxic tumor cells

3. Develop MSN capable of delivering drug/drug combinations

To investigate the effect …

Computational Approaches For Structure Based Drug Design And Protein Structure-Function Prediction, Sai Lakshmana Kumar Vankayala

USF Tampa Graduate Theses and Dissertations

This dissertation thesis consists of a series of chapters that are interwoven by solving interesting biological problems, employing various computational methodologies. These techniques provide meaningful physical insights to promote the scientific fields of interest. Focus of chapter 1 concerns, the importance of computational tools like docking studies in advancing structure based drug design processes. This chapter also addresses the prime concerns like scoring functions, sampling algorithms and flexible docking studies that hamper the docking successes. Information about the different kinds of flexible dockings in terms of accuracy, time limitations and success studies are presented. Later the importance of Induced fit …

N-Glycosylation Dictates Proper Processing Of Organic Anion Transporting Polypeptide 1b1, Juan Yao, Weifang Hong, Jiujiu Huang, Kai Zhan, Hong Huang, Mei Hong

School of Information Faculty Publications

Organic anion transporting polypeptides (OATPs) have been extensively recognized as key determinants of absorption, distribution, metabolism and excretion (ADME) of various drugs, xenobiotics and toxins. Putative N-glycosylation sites located in the extracellular loops 2 and 5 is considered a common feature of all OATPs and some members have been demonstrated to be glycosylated proteins. However, experimental evidence is still lacking on how such a post-translational modification affect the transport activity of OATPs and which of the putative glycosylation sites are utilized in these transporter proteins. In the present study, we substituted asparagine residues that are possibly involved in N-glycosylation with …

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Collected Faculty Scholarship

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

Solar Synthesis Of Acyl Hydroquinones And Their Bioactivity., Fernando De Leon, Shizue Mito

COURI Symposium Abstracts, Summer 2012

Without the Sun, we would not enjoy the benefits of life here on the Earth. This energy is essential and crucial for sustaining life: playing important roles in circadian rhythms and photosynthesis in plants. In our research, this endlessly renewable clean energy source is utilized for photo-Friedel-Crafts acylation of 1,4 - benzoquinones and 1,4 - naphthoquinones. Photo-Friedel-Crafts acylation was first discovered in 1891 and although there have been reported examples of acylated products, the substrates are still limited. In this project a variety of aldehydes having different substituents are examined, and bioassays were performed. While conventional methods for photochemistry use …

Effects Of Maternal Low Protein Diet On Expression Of Drug Transporters In The Blood-Brain Barrier Of Adult Offspring, Bonnie L. Hastings

Senior Theses

Adverse uterine environment, manifested as low birth weight (LBW), has been shown to predispose individuals to hypertension, diabetes, and obesity by mechanisms that are just beginning to be understood. One of the mechanisms is the dysregulation of the expression or function of drug transport proteins, such as the organic anion transporter (OAT) family, which are crucial for the transport of various endogenous and exogenous compounds into and out of all organs, especially the brain. Hence, we examined the status of select drug transporters in the blood-brain barrier (BBB), using a LBW rat model. Maternal low protein diet (LPD) during gestation …

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 …}

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, …

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. …

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 …

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 …

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 …

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 …

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 …

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 …

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.