Medicinal-Pharmaceutical Chemistry Commons^™

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: …

Hmba Is A Putative Hsp70 Activator Stimulating Hexim1 Expression That Is Down-Regulated By Estrogen, Rati Lama, Chunfang Gan, Nethrie Idippily, Viharika Bobba, David Danielpour, Monica Montano, Bin Su Ph.D.

Chemistry Faculty Publications

Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is identified as a novel inhibitor of estrogen stimulated breast cell growth, and it suppresses estrogen receptor-a transcriptional activity. HEXIM1 protein level has been found to be downregulated by estrogens. Recently, HEXIM1 has been found to inhibit androgen receptor transcriptional activity as well. Researchers have used Hexamethylene bisacetamide (HMBA) for decades to stimulate HEXIM1 expression, which also inhibit estrogen stimulated breast cancer cell gene activation and androgen stimulated prostate cancer gene activation. However, the direct molecular targets of HMBA that modulate the induction of HEXIM1 expression in mammalian cells have not been identified. Based …

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. …

Chemical Profiling And Chemical Standardization Of Vitex Negundo Using 13c Nmr, Fabian M. Dayrit, Lolita G. Lagurin, John Daniel J. Magsalin, Anthony R. Zosa

Chemistry Faculty Publications

Chemical profiling and standardization of the defatted methanol extract of the leaves of Vitex negundo L. were carried out using 13C nuclear magnetic resonance (NMR) analysis followed by chemometric analysis of the chemical shift data. Chemical profile was obtained using a k-means cluster profile and chemical standardization which was achieved using a multivariate control chart. The V. negundo samples were made up of four groups: the training set, submitted samples from production farms, commercial samples, such as tablets, capsules and teas, and experimental samples (samples which were allowed to degrade). Four groups were generated in k-means cluster, which generally corresponded …

Phage Display To Identify Functional Resistance Mutations To Rigosertib, Nedim Filipovic

CMC Senior Theses

In vitro protein selection has had major impacts in the field of protein engineering. Traditional screens assay individual proteins for specific function. Selection, however, analyzes a pool of mutants and yields the best variants. Phage display, a successful selection technique, also provides a reliable link between variant phenotype and genotype. It can also be coupled with high throughput sequencing to map protein mutations; potentially highlighting vital mutations in variants. We propose to apply this technique to cancer therapy. RAF, a serine/threonine kinase, is critical for cell regulation in mammals. RAF can be activated by oncogenic RAS, found in over 30% …

Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii

Dissertations

The studies presented in section 1 (Chapters I-IV) focus on the design and development of nucleic acid four-way junctions (4WJs) to target a member of the high mobility group (HMG) proteins, the proinflammatory cytokine high mobility group box 1 protein (HMGB1). In the present study, hybrid PNA-DNA 4WJs based on a model DNA 4WJ were constructed to improve the thermal stability of 4WJs while maintaining strong binding affinity toward HMGB1. An electrophoretic mobility shift assay (EMSA) was used to examine the binding affinity of an isolated DNA binding domain of HMGB1, the HMGB1 b-box (HMGB1b), toward a set of PNA-DNA …

2016-01-A3dsrinp-Csc-Sta-Cmb-522-Bps-542, Raymond Pulver, Neal Buxton, Xiaodong Wang, John Lucci, Jean Yves Hervé, Lenore Martin

Bioinformatics Software Design Projects

Cholesterol is carried and transported through bloodstream by lipoproteins. There are two types of lipoproteins: low density lipoprotein, or LDL, and high density lipoprotein, or HDL. LDL cholesterol is considered “bad” cholesterol because it can form plaque and hard deposit leading to arteries clog and make them less flexible. Heart attack or stroke will happen if the hard deposit blocks a narrowed artery. HDL cholesterol helps to remove LDL from the artery back to the liver.

Traditionally, particle counts of LDL and HDL plays an important role to understanding and prediction of heart disease risk. But recently research suggested that …

Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying

Honors Thesis

The Zn(II) metal ion has been shown to interact with Islet Amyloid Polypeptide (IAPP), a protein implicated in the progression of Type II Diabetes Mellitus, in such a way as to prevent the protein from aggregating into toxic fibers. We set out to find whether other metal ions might similarly prevent IAPP aggregation. Using Thioflavin T (ThT) spectroscopic assays, which measure fluorescence of ThT upon binding to aggregated IAPP, we observed a decrease in aggregation when incubated with Zn(II), Cu(II), Ni(II), and Sn(II). Atomic Force Microscopy (AFM), which can visualize fibril formation, revealed that the metals were not inhibiting IAPP …

Binding Of Oxaliplatin And Its Analogs With Dna Nucleotides At Variable Ph And Concentration Levels, Rippa Sehgal

Masters Theses & Specialist Projects

Oxaliplatin is one of the three FDA-approved platinum anticancer drugs and considered a third generation drug, discovered after the first generation drug cisplatin and second generation drug carboplatin. It is known to react with proteins and DNA nucleotides in the body. Reaction with DNA occurs primarily at guanosine residues and secondarily at adenine residues for oxaliplatin and other platinum drugs. We have previously studied oxaliplatin and an analog with additional steric hindrance in the amine ligand and found that the analog had different reactivity with methionine. Now, we have prepared oxaliplatin and its three analogs Pt(Me2dach)(ox), Pt(en)(ox) and Pt(Me4en)(ox) and …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen

Dissertations and Theses (Open Access)

The past decade has witnessed an era of RNA biology; despite the considerable discoveries nowadays, challenges still remain when one aims to screen RNA-interacting small molecule or RNA-interacting protein. These challenges imply an immediate need for cost-efficient while predictive computational tools capable of generating insightful hypotheses to discover novel RNA-interacting small molecule or RNA-interacting protein. Thus, we implemented novel computational models in this dissertation to predict RNA-ligand interactions (Chapter 1) and RNA-protein interactions (Chapter 2).

Targeting RNA has not garnered comparable interest as protein, and is restricted by lack of computational tools for structure-based drug design. To test the potential …

The Use Of Shape Memory Polymers As A Tool To Study Human Fibrosarcoma And Murine Mesenchymal Stem Cell Migration, Justin N. Elkhechen

Renée Crown University Honors Thesis Projects - All

Shape memory polymers (SMPs) are a class of “smart” materials that can transform between two distinct conformations through external stimuli, such as heat or electricity. Their usage in bioengineering has led to a promising field of research that lies at the interface of cell and mechanobiology, potentially providing insight into cancer therapies and tissue development—two processes that exist in dynamic environments in vivo. The present work involves creating new, shape changing, scaffolds for studies to analyze cell migration upon changes to the environmental topography. Specifically, this Capstone has been primarily focused on the development of a “half and half” fibrous …

Ultrafast Interfacial Electron Transfer Across Molecule-Tio2 Nanocomposites: Towards Solar Cells And Two Photon Absorption, Edwin Mghanga

Dissertations

Interfacial charge transfer (ICT) across the molecule-TiO2 nanoparticle interface has gained enormous research attention for applications in dye sensitized solar cells (DSSC), photo-catalysis, water splitting and nonlinear optics. DSSCs are promising clean alternative energy sources. However, current DSSCs suffer from lower efficiencies and higher cost. Better understanding of the ICT processes in DSSCs can help solve these problems. We have used two strategies to understand ICT in the context of DSSCs. Firstly, we used a computationally validated anchor group, acetylacetonate (acac) to bind molecules to the semiconductor surface and facilitate charge separation. Secondly, we used natural dye sensitizers, …

Branching Into Rnai: Synthesis, Characterization And Biology Of Branch And Hyperbranch Sirnas, Anthony Muriithi Maina

Seton Hall University Dissertations and Theses (ETDs)

The cancer epidemic continues to afflict millions of humans world-wide each year and despite a renewed hope with the development of new and improved forms of therapy, a cure for cancer remains an elusive goal. This is partly related to the rise of resilient forms of tumors that have evolved with resistance towards conventional chemotherapy and radiation treatments. Moreover, these non-specific therapeutic regimens are highly toxic, leading to severe immunosuppressive effects which poisons the body and compromises the road towards remission. In an effort to mitigate these limitations, cancer-targeting approaches are currently experiencing a renaissance in the translation of new …

Metal Stopping Reagents Facilitate Discontinuous Activity Assays Of The De Novo Purine Biosynthesis Enzyme Pure, Kelly L. Sullivan, Loredana C. Huma, Elwood Mullins, Michael E. Johnson, T. Joseph Kappock

Department of Biochemistry Faculty Publications

The conversion of 5-aminoimidazole ribonucleotide (AIR) to 4-carboxy-AIR (CAIR) represents an unusual divergence in purine biosynthesis: microbes and nonmetazoan eukaryotes use class I PurEs while animals use class II PurEs. Class I PurEs are therefore a potential antimicrobial target; however, no enzyme activity assay is suitable for high throughput screening (HTS). Here we report a simple chemical quench that fixes the PurE substrate/product ratio for 24 h, as assessed by the Bratton-Marshall assay (BMA) for diazotizable amines. The ZnSO₄ stopping reagent is proposed to chelate CAIR, enabling delayed analysis of this acid-labile product by BMA or other HTS methods

Further Characterization Of A Secreted Lipase From The Human Pathogen Leishmania Donovani By Determining The Effect Of Various Metal Ions On Its Enzymatic Activity., Lana Hoertz

Pell Scholars and Senior Theses

Leishmania donovani, a protozoan parasite, is the causative agent of the often fatal disease visceral leishmaniasis. The current treatments available are minimal and toxic to the patient. It has been shown that these organisms exhibit lipolytic activity during their growth in vitro. Lipases are enzymes that are known to aid in the development and virulence of several pathogenic organisms such as Candida albicans and Staphylococcus warneri. Little information is known, however, about the role of lipases in Leishmania species. We hypothesize that lipase may play a part in Leishmania's ability to survive within the human host as well as its …

A Supramolecular Strategy To Assemble Multifunctional Viral Nanoparticles, Limin Chen, Xia Zhao, Yuan Lin, Yubin Huang, Qian Wang

Faculty Publications

Using a one-pot approach driven by the supramolecular interaction between β-cyclodextrin and adamantyl moieties, multifunctional viral nanoparticles can be facilely formulated for biomedical applications.

Amalgamation Of Nucleosides And Amino Acids In Antibiotic Biosynthesis, Sandra H. Barnard

Theses and Dissertations--Pharmacy

The rapid increase in antibiotic resistance demands the identification of novel antibiotics with novel targets. One potential antibacterial target is the biosynthesis of peptidoglycan cell wall, which is both ubiquitous and necessary for bacterial survival. Both the caprazamycin-related compounds A-90289 and muraminomicin, as well as the capuramycin-related compounds A-503083 and A-102395 are potent inhibitors of the translocase I enzyme, one of the key enzymes required for cell wall biosynthesis. The caprazamycin-related compounds contain a core nonproteinogen b-hydroxy-a-amino acid referred to as 5’-C-glycyluridine (GlyU). Residing within the biosynthetic gene clusters of the aforementioned compounds is a shared open reading …

Breast Tumour Initiating Cell Fate Is Regulated By Microenvironmental Cues From An Extracellular Matrix, Sharmistha Saha, Pang-Kuo Lo, Xinrui Duan, Hexin Chen, Qian Wang

Faculty Publications

Cancer stem cells, also known as tumour-initiating cells (TICs), are identified as highly tumorigenic population within tumours and hypothesized to be main regulators in tumour growth, metastasis and relapse. Evidence also suggests that a tumour microenvironment plays a critical role in the development and progression of cancer, by constantly modulating cell–matrix interactions. Scientists have tried to characterize and identify the TIC population but the actual combination of extracellular components in deciphering the fate of TICs has not been explored. The basic unanswered question is the phenotypic stability of this TIC population in a tissue extracellular matrix setting. The in vivo …

Discrimination Of Colon Cancer Stem Cells Using Noncanonical Amino Acid, Xinrui Duan, Honglin Li, Hexin Chen, Qian Wang

Faculty Publications

Cancer stem cells (CSCs) may be responsible for tumor recurrence. Metabolic labelling of newly synthesized proteins with non-canonical amino acids allows us to discriminate CSCs in mixed populations due to the quiescent nature of these cells.

Synthesis Of S-Ribosyl-L-Homocysteine And Analogs Modified At The Homocysteine-C3 Position, Ruoyi Liu

Master's Theses

Quorum sensing (QS) is a process of bacterial cell-to-cell communication that conveys population density information in order to coordinate gene expression to produce synchronized behaviors. QS regulates the expression of virulence genes in many species of bacteria; hence, the manipulation of QS pathways may lead to treatment options against many bacterial diseases. The LuxS enzyme converts S-ribosyl-L-homocysteine (SRH) into homocysteine (HCys) and 4(S),5-dihydroxypentane-2,3-dione (DPD), which is the precursor of autoinducer-2 (AI-2). Thus, inhibitors of LuxS could prevent QS by halting the conversion of SRH to AI-2 rendering the cell “uncommunicative”. This work shows the successful chemical synthesis …

Cell Migration Dynamics After Alteration Of Cell-Cell Contacts In Fibrosarcoma And Glioblastoma Cell Lines, Hassan S. Rizvi, Ronald K. Gary

Undergraduate Research Opportunities Program (UROP)

Cell migration is a vital component of metastasis. In this study, our intent was to study cell migration by alteration of the Wnt/GSK-3 Pathway. Since BeSO4 is a known GSK-3 kinase inhibitor, we hypothesized that this agent would cause cell migration to decrease as a result of β-catenin stabilization. Two human cell lines, HT-1080 (fibrosarcoma) and A172 (glioblastoma), were used to observe migration levels in the presence and absence of BeSO4. Our results show that cell migration is diminished for cells that were pre-treated with BeSO4, in comparison to the untreated (control) cells.

Organometallic Iron(Iii)-Salophene Exerts Cytotoxic Properties In Neuroblastoma Cells Via Mapk Activation And Ros Generation, Kyu Kwang Kim, Rakesh K. Singh, Robert M. Strongin, Richard G. Moore, Laurent Brard, Thilo S. Lange

Chemistry Faculty Publications and Presentations

The objective of the present study was to investigate the specific effects of Iron(III)-salophene (Fe-SP) on viability, morphology, proliferation, cell cycle progression, ROS generation and pro-apoptotic MAPK activation in neuroblastoma (NB) cells. A NCI-DTP cancer screen revealed that Fe-SP displayed high toxicity against cell lines of different tumor origin but not tumor type-specificity. In a viability screen Fe-SP exhibited high cytotoxicity against all three NB cell lines tested. The compound caused cell cycle arrest in G1 phase, suppression of cells progressing through S phase, morphological changes, disruption of the mitochondrial membrane depolarization potential, induction of apoptotic markers as well as …

Antimicrobial Activity Of D-Lenolate®, Andy Phui

UNLV Theses, Dissertations, Professional Papers, and Capstones

Olive trees are one of the most important fruit trees in the Mediterranean. Although not validated by research, olive leaves are traditionally believed to fight off fever and infections. It has been shown that olive leaf extracts possess antimicrobial activity. Olive leaf extracts contain polyphenols. One of the major phenolic compounds is oleuropein. Oleuropein and other polyphenols have been shown to exhibit antimicrobial activity. East Park Research (EPR) developed an extraction process that they claim does not alter the chemical composition of the olive leaves. The extract is known by the commercial name d-lenolate®. Studies have provided evidence that d-lenolate®, …

Identifying Biomarkers For Resistance To Novel Cisplatin Analogues In Human Lung, Breast And Prostate Cancers, Becky Michelle Hess

UNLV Theses, Dissertations, Professional Papers, and Capstones

Cisplatin is a common therapeutic agent used in cancer treatment. Unfortunately, resistance to cisplatin in addition to severe side effects limits its use in cancer treatment. Two novel cisplatin analogues, 4DB and 4TB were shown to have varying cytotoxicity in lung, breast and prostate cancer cells. The hypothesis for this study states that the differences in 4DB and 4TB cytotoxicity among different tissue types is due to the type and efficiency of DNA repair mechanisms involved in response to these drugs.

To test the hypothesis, proteins involved in the rate limiting step of nucleotide excision repair (NER) and mismatch repair …

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.

Altered Phosphorylation Of [Beta]-Catenin In Glucocorticoid Treated 235-1 Rat Pituitary Tumor Cells, Susie K. Saunders

Theses, Dissertations and Capstones

Beta-catenin is an essential cell adhesion and signaling protein, associated with high prolactin levels in rat pituitary tumor cells. It has been shown that phosphorylation affects the location and activity of b-catenin. Glycogen synthase kinase (GSK3-b) is a serine-threonine kinase that phosphorylates b-catenin on N-terminal residues, targeting it for proteasomal degradation. Studies have shown that C-terminal tyrosine phosphorylation decreases the association of b-catenin with cadherin. In 235-1 rat pituitary tumor cells, our lab has shown that the glucocorticoid analog dexamethasone (Dex) decreases the half- life of b-catenin while increasing the activity of GSK3-b. The current study was undertaken to examine …

Affinity Chromatography: A Review Of Clinical Applications, David S. Hage

David Hage Publications

Affinity chromatography is a type of liquid chromatography that makes use of biological-like interactions for the separation and specific analysis of sample components. This review describes the basic principles of affinity chromatography and examines its use in the testing of clinical samples, with an emphasis on HPLCbased methods. Some traditional applications of this approach include the use of boronate, lectin, protein A or protein G, and immunoaffinity supports for the direct quantification of solutes. Newer techniques that use antibody-based columns for on- or off-line sample extraction are examined in detail, as are methods that use affinity chromatography in combination with …

Localization Of Sodium, Potassium-Adenosine Triphosphatase In The Cerebral Cortex Of Developing Rats, Maki Ujiie

Loma Linda University Electronic Theses, Dissertations & Projects

Active transport via Na⁺, K⁺-ATPase plays an important role in establishing and maintaining proper ionic gradient across all mammalian cell membranes. A strict regulation of Na⁺, and K⁺ ion levels is especially important in excitable cells such as neurons and myocytes. Inhibition of the enzyme is associated with several pathological conditions and has serious detrimental effects on cerebral cortical cells. Yet the enzyme appears to be limited in amount and distribution in newborn rats. In this study, Na_⁺, K⁺- ATPase expression and distribution in early postnatal rats were studied …

Structural Characterization Of A Novel Inhibitor Of Hiv Reverse Transcriptase (Hiv Rt), Greggory Jon Woitte

Chemistry & Biochemistry Theses & Dissertations

Human immunodeficiency virus (HIV) infections have become a leading cause of death among young people in the United States today. As the number of HIV infections increases, so too does the cost of treatment. Together, these numbers have prompted an increase in the development of pharmaceutical interventions. HIV reverse transcriptase (HIV RT) has become a suitable target for drug therapy because it is the sole enzyme responsible for HIV replication.

Fucoidan, a sulfated polysaccharide isolated from the brown algae Fucus vesiculosus, has been shown to block a variety of cell adhesion related events including metastasis. In addition, fucoidan has also …