Medicinal-Pharmaceutical Chemistry Commons^™

Examination Of An Aloe Vera Galacturonate Polysaccharide Capable Of In Situ Gelation For The Controlled Release Of Protein Therapeutics, Shawn David Mcconaughy

Dissertations

A therapeutic delivery platform has been investigated with the ultimate goal of designing a sustained protein release matrix utilizing an in-situ gelling, acidic polysaccharide derived from the Aloe vera plant. The Aloe vera polysaccharide (AvP) has been examined in order to determine how chemical composition, structure, molecular weight and solution behavior affect gelation and protein/peptide delivery. Correlations are drawn between structural characteristics and solution behavior in order to determine the impact of polymer conformation and solvation on gel formation under conditions designed to simulate nasal applications. Steady state and dynamic rheology, classic and dynamic light scattering, zeta potential, pulse field …

Oriented Cell Growth On Self-Assembled Bacteriophage M13 Thin Films, Jianhua Rong, L. Andrew Lee, Kai Li, Brandon Harp, Charlene M. Mello, Zhongwei Niu, Qian Wang

Faculty Publications

Fibrillar M13 bacteriophages were used as basic building blocks to generate thin films with aligned nanogrooves, which, upon chemical grafting with RGD peptides, guide cell alignment and orient the cell outgrowth along defined directions.

A Study On The Protein Interaction With Different Platinum Compounds, Nayna Kotadia

Masters Theses & Specialist Projects

Since the discovery of anti-tumor activity of cisplatin in 1960, significant progress has been made in treating metastatic or advanced cancer with cisplatin and platinum compounds. Platinum compounds covalently bind to DNA and disrupt DNA function. They are also known to bind with amino acids like methionine, histidine and cysteine to form cisplatin-protein adducts which are responsible for most of its cytotoxicity and side effects. Recent articles on cisplatin-protein have shown that adding bulky adjuncts to cisplatin or using different platinum compounds varies the degree and extent of reaction thus possibly reducing cisplatin resistance and side effects.

One of the …

Preparation Of Halogenated Derivatives Of Thiazolo[5,4-D]Thiazole Via Direct Electrophilic Aromatic Substitution, Vladimir Benin, Alan T. Yeates, Douglas Dudis

Chemistry Faculty Publications

Chlorination and bromination reactions of thiazolo[5,4-d]thiazole led to the generation of its mono- and dihalogenated derivatives. These are the first instances of successful direct electrophilic aromatic substitution in the thiazolo[5,4-d]thiazole ring system. X-ray analysis demonstrates that both 2-bromothiazolo[5,4-d]-thiazole and 2,5-dibromothiazolo[5,4-d]thiazole are planar structures, with strongly manifested π-stacking in the solid state. Theoretical analysis of the pyridine-catalyzed halogenation (MP2/6-31+G(d) and B3LYP/6-31+G(d)calculations) reveals that introduction of one halogen actually leads to a slightly enhanced reactivity towards further halogenation. Several halogenation mechanisms have been investigated: 1) The direct C-halogenation with N-halopyridine as electrophile; …

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 …

C–N Bond Rotation And E–Z Isomerism In Some N-Benzyl-N-Methylcarbamoyl Chlorides: A Dft Study, Michael Horwath, Vladimir Benin

Chemistry Faculty Publications

The current report presents the first theoretical study of the restricted CN bond rotation in carbamoyl chlorides. Several N-benzyl-N-methylcarbamoyl chlorides were investigated, with varying pattern of substitution in the aromatic ring. Optimizations and frequency calculations were conducted employing DFT at the B3LYP/6-31+G(d) level of theory. Each of the studied structures exhibits a pair of rotamers (s-Z and s-E), generated upon rotation around the C(O)N bond. The s-E isomer is the global minimum in every case, but the preference for it is usually less than 1 kcal/mol. Two possible transition state structures were identified …

Identification And Analysis Of Prohibitin In B16 Mouse Melanoma Cells, Christopher Francis

Theses, Dissertations and Capstones

Prohibitin, a highly conserved protein found in eukaryotic cells, has been found in recent years to possess a wide variety of functions in the cell. Whereas the mechanisms by which the protein functions are still largely unknown, it is clear that prohibitin possesses very strong anti-proliferative properties in the cell, as well as potentially both nuclear and mitochondrial functions based upon its movement and localization upon apoptotic signaling. Upon treatment with retinoic acid, transformed B16 mouse melanoma cells also indicate a differential expression of prohibitin in which production of the protein is increased. The purpose of this work was to …

Phosphorylation Of Claudin-5 And Occludin By Rho Kinase In Brain Endothelial Cells, Masaru Yamamoto, Servio H. Ramirez, Shinji Sato, Tomomi Kiyota, Ronald Cerny, Kozo Kaibuchi, Yuri Persidsky, Tsuneya Ikezu

Ronald Cerny Publications

Critical to the proper maintenance of blood-brainbarrier (BBB) integrity are the endothelial tight junctions (TJs). Posttranslational modifications of essential endothelial TJ proteins, occludin and claudin-5, contribute and possibly disrupt BBB integrity. Our previous work has shown that Rho kinase (RhoK) activation mediates occludin and claudin-5 phosphorylation resulting in diminished barrier tightness and enhanced monocyte migration across BBB in the setting of human immunodeficiency virus-1 encephalitis (HIVE). To determine whether RhoK can directly phosphorylate TJ proteins, we examined phosphorylation of cytoplasmic domains of recombinant claudin- 5 and occludin by RhoK. We found that RhoK predominately phosphorylated two sites on occludin (T382 …

Synthesis Towards Novel 1,3-Azaborine Heterocycles As Potential Dual-Mode Hiv-1 Protease Inhibitors, Amanda Blackmore

Undergraduate Honors Theses

Drug discovery has resulted in many life-saving therapies, making a great impact on modem medicine and the human condition. Even though new therapies are available many drugs are highly susceptible to resistance development, have poor bioavailability, and some of them are toxic. HIV-I protease inhibitors presently on the market show high specificity but have low bioavailability and high toxicity. Furthermore, the available drugs have a very low affinity for mutant forms of HIV -1 protease. Recent studies have shown that boronated HIV-I protease inhibitors, which demonstrate both competitive and associative inhibition, have a higher affinity for HIV-I protease at lower …

Synthesis Of 5,6 Dihydropyran-2-Ones As Potential Inhibitors Of Hiv-1 Protease, Jesse Lee Nye

Undergraduate Honors Theses

HIV/ AIDS has affected about 40 million people. One type of drug that is used to treat HIV/AIDS is a protease inhibitor. HIV-I protease is an enzyme responsible for the release of mature HIV viral particles in the body. HIV-I protease eventually becomes resistant to the inhibitors that are used as drugs and new inhibitors are needed. This research builds on a previous research effort, in which structures for HIV -1 protease inhibitors were designed using molecular modeling methods, including neural networks. These inhibitors were designed to possess better inhibitory properties, and possibly have increased bioavailability and less toxicity than …

Analysis Of Residual Solvents In Pharmaceuticals By Comprehensive Two-Dimensional Gas Chromatography, Cristina Marie Crimi

Seton Hall University Dissertations and Theses (ETDs)

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Synthesis Of Multifunctional Nanogels Using A Protected Macromonomer Approach, Neetu Singh, L. Andrew Lyon

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Nanoparticles possessing multiple functionalities provide synthetic handles for varied surface chemistries, making them useful for a range of applications such as biotargeting and drug delivery. However, the combination of interfering functionalities on the same particle is often challenging. We have employed a synthetic scheme involving chemical protection/deprotection to combine interfering functional groups on the same hydrogel nanoparticle. The synthesis of amine-containing poly(N-isopropylacrylamide) nanogels was carried out via free radical precipitation polymerization by incorporating a Fmoc-protected amine poly(ethylene glycol) (PEG) macromonomer. The Fmoc group was then removed to obtain free amines, which were shown to be available for conjugation. We further …

Systematic Synthesis And Study Of The Structure-Property Relationships Of Arylene Vinylene Polymers., Patrick Lynch

Doctoral

Much is known about the electronic, vibrational and steric effects resulting from the addition of differing organic functional groups as side chains, to the parent conjugated polymer. However the same cannot be said about the substitution of constituents of the polymer backbone itself. To this end a study is presented here which systematically studies the effects of naphthalene and anthracene substitution of the properties of poly phenylene vinylene (PPV) derivative conjugated polymers. The synthesis by the Witting-Horner reaction of derivatives is presented whereby the phenylene units of the PPV structure are methodically substituted by naphthylene and anthrylene units to form …

Phosphorylation Of Muc1 By Met Modulates Interaction With P53 And Mmp1 Expression, Pankaj K. Singh, Michelle E. Behrens, John P. Eggers, Ronald Cerny, Jennifer M. Bailey, Kandavel Shanmugam, Sandra J. Gendler, Eric P. Bennett, Michael A. Hollingsworth

Ronald Cerny Publications

MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time …

Unsymmetric Aryl–Alkyl Disulfide Growth Inhibitors Of Methicillin-Resistant Staphylococcus Aureus And Bacillus Anthracis, Edward Turos, Kevin D. Revell, Praveen Ramaraju, Danielle A. Gergeres, Kerriann Greenhalgh, Ashley Young, Nalini Sathyanarayan, Sonja Dickey, Daniel Lim, Mamoun M. Alhamadsheh, Kevin A. Reynolds

Chemistry Faculty Publications and Presentations

This study describes the antibacterial properties of synthetically-produced mixed aryl alkyl disulfide compounds as a means to control the growth of Staphylococcus aureus and Bacillus anthracis. Some of these compounds exerted strong in vitro bioactivity. Our results indicate that among the twelve different aryl substituents examined, nitrophenyl derivatives provide the strongest antibiotic activities. This may be the result of electronic activation of the arylthio moiety as a leaving group for nucleophilic attack on the disulfide bond. Small alkyl residues on the other sulfur provide the best activity as well, which for different bacteria appears to be somewhat dependent on …

Reduced Acute Inflammatory Responses To Microgel Conformal Coatings, Amanda W. Bridges, Neetu Singh, Kellie L. Burns, Julia E. Babensee, L. Andrew Lyon, Andrés J. García

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Implantation of synthetic materials into the body elicits inflammatory host responses that limit medical device integration and biological performance. This inflammatory cascade involves protein adsorption, leukocyte recruitment and activation, cytokine release, and fibrous encapsulation of the implant. We present a coating strategy based on thin films of poly(N-isopropylacrylamide) hydrogel microparticles (i.e. microgels) cross-linked with poly(ethylene glycol) diacrylate. These particles were grafted onto a clinically relevant polymeric material to generate conformal coatings that significantly reduced in vitro fibrinogen adsorption and primary human monocyte/macrophage adhesion and spreading. These microgel coatings also reduced leukocyte adhesion and expression of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, …