Medicinal-Pharmaceutical Chemistry Commons^™

Organocatalyzed Synthesis Of Epoxides From Chalcones Utilizing Amino Acids, Sabrina N. Kegeler

Masters Theses

The epoxide functional group is important throughout the chemical and pharmaceutical industries, as well as in nature. In the chemical industry, epoxides are present in resins and fragrances. In the pharmaceutical industry, epoxide-containing compounds are used as intermediates in the manufacturing of drugs. In nature, many natural products contain epoxide groups and are used for medicinal purposes, and for models to create synthetic molecules.

One approach to epoxide synthesis involves the use of an alkene precursor, a base, and an oxidizing agent. This is where my investigations began. The first step was to optimize the epoxidation reaction, examining substrate scope, …

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 …

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: …

Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham

FIU Electronic Theses and Dissertations

Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca²⁺ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca²⁺ and/or Mg²⁺ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca²⁺ and/or Mg²⁺ binding to DREAM …

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 …

Peptide Arrays For Detecting Naphthenic Acids In Oil Sands Process Affected Water, Kamaljit Kaur, Subir Bhattacharjee, Rajesh G. Pillai, Sahar Ahmed, Sarfuddin Azmi

Pharmacy Faculty Articles and Research

Naphthenic acids (NAs) are water-soluble components of petroleum. The characterization and quantification of NAs by analytical methods have proved quite challenging, whilst the toxic effects of these water-soluble compounds on a variety of organisms adversely affecting reproduction and steroid production is becoming apparent. In this study, we report a fluorescence-based competitive binding method for rapid sensing of the presence of NAs using cellulosic peptide array strips as sensors. The peptide array was designed from sequences derived from the estrogen receptor (ER). Several of these peptides were able to detect the presence of NAs at low micromolar (∼5 mg L^{−1 …}

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres

Doctoral Dissertations

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of …

Syntheses Of Precursors To Fluorine-18 Labeled Pet Imaging Agents, Lindsay B. Boling

Chancellor’s Honors Program Projects

No abstract provided.

The Use Of A Ditopic Gd(Iii) Paramagnetic Probe For Investigating Α-Bungarotoxin Surface Accessibility, Andrea Bernini, Ottavia Spiga, Vincenzo Venditti, Filippo Prischi, Mauro Botta, Gianluca Croce, Angela Pui-Ling Tong, Wing-Talk Wong, Neri Niccolai

Vincenzo Venditti

Protein surface accessibility is a critical parameter which drives all intermolecular interaction processes. In this respect a big deal of information has been derived by analyzing paramagnetic perturbation profiles obtained from NMR protein spectra, particularly in the case that the effects due to different soluble paramagnets can be compared. Here Gd2L7, a neutral ditopic paramagnetic NMR probe, has been characterized in terms of structure and relaxivity and its paramagnetic perturbations on α-bungarotoxin CαH signals in 1H–13C HSQC (heteronuclear single quantum coherence) spectra have been analyzed. Then, these signal attenuations have been compared with the ones previously obtained in the presence …

An Efficient Protocol For Incorporation Of An Unnatural Amino Acid In Perdeuterated Recombinant Proteins Using Glucose-Based Media, Vincenzo Venditti, Nicolas L. Fawzi, G. Marius Clore

Vincenzo Venditti

The in vivo incorporation of unnatural amino acids into proteins is a well-established technique requiring an orthogonal tRNA/aminoacyl-tRNA synthetase pair specific for the unnatural amino acid that is incorporated at a position encoded by a TAG amber codon. Although this technology provides unique opportunities to engineer protein structures, poor protein yields are usually obtained in deuterated media, hampering its application in the protein NMR field. Here, we describe a novel protocol for incorporating unnatural amino acids into fully deuterated proteins using glucose-based media (which are relevant to the production, for example, of amino acid-specific methyl-labeled proteins used in the study …

Detection Of Protein By Microdrop Analysis, Yogeshkumar Radadiya

All Capstone Projects

Analysis of protein depends particularly on protein concentration. Protein concentration measurement is the most important part in the research work to conduct protein-related studies. Although there are many methods available for this purpose, each method has certain limitations. The aim of the experiment is to develop either new or modified analytical method for the analysis and detection of protein using newly introduced micro-plate reader equipped with Take-3 microplate with the help of Gen-5 software. An ideal assay should be simple and easy to carry out. Another aspect to be taken into consideration are low inference, stability of measured components and …

Pharmacological Chaperoning In Fabry Disease, Jerome Rogich

Masters Theses 1911 - February 2014

Fabry Disease is an X-­‐linked lysosomal storage disorder characterized by a variety of symptoms including hypohydrosis, seizures, cardiac abnormalities, skin lesions, and chronic pain. These symptoms stem from a lack of functional endogenous α-­‐ Galactosidase A (α-­GAL), which leads to an accrual of its natural substrate. The severity of the disease symptoms can be directly correlated with the amount of residual enzyme activity. It has been shown that an imino sugar, 1-deoxygalactonojirimycin (DGJ), can increase enzymatic activity and clear excess substrate. This pH-­‐dependent chaperoning phenomenon is believed to arise from the presence of aspartic acid 170 in the active site. …

Automated Sequence- And Stereo-Specific Assignment Of Methyl-Labeled Proteins By Paramagnetic Relaxation And Methyl–Methyl Nuclear Overhauser Enhancement Spectroscopy, Vincenzo Venditti, Nicolas L. Fawzi, G. Marius Clore

Vincenzo Venditti

Methyl-transverse relaxation optimized spectroscopy is rapidly becoming the preferred NMR technique for probing structure and dynamics of very large proteins up to ~1 MDa in molecular size. Data interpretation, however, necessitates assignment of methyl groups which still presents a very challenging and time-consuming process. Here we demonstrate that, in combination with a known 3D structure, paramagnetic relaxation enhancement (PRE), induced by nitroxide spin-labels incorporated at only a few surface-exposed engineered cysteines, provides fast, straightforward and robust access to methyl group resonance assignments, including stereoassignments for the methyl groups of leucine and valine. Neither prior assignments, including backbone assignments, for the …

A Structurally Driven Analysis Of Thiol Reactivity In Mammalian Albumins, Ottavia Spiga, Domenico Summa, Simone Cirri, Andrea Bernini, Vincenzo Venditti, Matteo De Chiara, Raffaella Priora, Simona Frosail, Antonios Margaritis, Danila Di Giuseppe, Paolo Di Simplicio, Neri Niccolai

Vincenzo Venditti

Understanding the structural basis of protein redox activity is still an open question. Hence, by using a structural genomics approach, different albumins have been chosen to correlate protein structural features with the corresponding reaction rates of thiol exchange between albumin and disulfide DTNB. Predicted structures of rat, porcine, and bovine albumins have been compared with the experimentally derived human albumin. High structural similarity among these four albumins can be observed, in spite of their markedly different reactivity with DTNB. Sequence alignments offered preliminary hints on the contributions of sequence-specific local environments modulating albumin reactivity. Molecular dynamics simulations performed on experimental …

Protein Adducts Of Iso[4]Levuglandin E2, A Product Of The Isoprostane Pathway, In Oxidized Low Density Lipoprotein, Robert G. Salomon, Wei Sha, Cynthia Brame, Kamaljit Kaur, Ganesamoorthy Subbanagounder, June O'Neil, Henry F. Hoff, L. Jackson Roberts Ii

Pharmacy Faculty Articles and Research

Levuglandin (LG) E₂, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H₂, avidly binds to proteins. That LGE₂-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE₂-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now …