Medicinal-Pharmaceutical Chemistry Commons^™

Donnan Potential Across The Outer Membrane Of Gram-Negative Bacteria And Its Effect On The Permeability Of Antibiotics, Olaniyi Alegun, Ankit Pandeya, Jian Cui, Isoiza Ojo, Yinan Wei

Chemistry Faculty Publications

The cell envelope structure of Gram-negative bacteria is unique, composed of two lipid bilayer membranes and an aqueous periplasmic space sandwiched in between. The outer membrane constitutes an extra barrier to limit the exchange of molecules between the cells and the exterior environment. Donnan potential is a membrane potential across the outer membrane, resulted from the selective permeability of the membrane, which plays a pivotal role in the permeability of many antibiotics. In this review, we discussed factors that affect the intensity of the Donnan potential, including the osmotic strength and pH of the external media, the osmoregulated periplasmic glucans …

Design, Synthesis And Evaluation Of Molecules With Selective And Poly-Pharmacological Actions At D1r, D3r And Sigma Receptors, Pierpaolo Cordone

Dissertations, Theses, and Capstone Projects

The dopamine D3 receptor (D3R) is one of the most studied receptors involved in drug addiction. One of the most common strategies to treat substance use disorders is via D3R antagonism. The majority of the D3R antagonists synthesized so far have poor pharmacokinetic properties and/or lack selectivity toward D3R. In this thesis, the design, synthesis and biological evaluation of novel molecules that target the dopamine D1 receptor (D1R), D3R and the serendipitous discovery of molecules that target s receptors will be described.

Chapter 1 presents a survey of the fundamental pharmacology of D1R, D3R and s receptors and the therapeutic …

Synthetic And Biological Studies On Benzazepine Derivatives As Dopamine Receptor Ligands, Rajan Giri

Dissertations, Theses, and Capstone Projects

Dopamine (DA) receptors, members of the G-protein coupled receptors (GPCRs) family, are divided in two groups based on their transmembrane structural homology domains: D1R-like (D1R, D5R sub-types) and D2R-like DA receptors (D2R, D3R and D4R sub-types). Disturbances in dopaminergic neurotransmission are associated with several CNS disorders. Hence, DA receptor selective ligands have been sought as pharmacological agents to normalize perturbations in the dopaminergic system. Despite several notable efforts, the discovery of highly selective ligands for dopamine receptor sub-types has proved challenging due to close transmembrane structural similarity, especially between DA receptor sub-types within the same group.

The 1-phenylbenzazepine scaffold is …

The Emerging Applications Of Sulfur (Vi) Fluorides In Catalysis, Nicholas Ball, Cayo Lee, Jonathan E. Elisabeth, Nathan C. Friede, Glenn M. Sammis

Pomona Faculty Publications and Research

The past decade has witnessed remarkable growth of catalytic transformations in organic sulfur(VI) fluoride chemistry. This Perspective concentrates exclusively on foundational examples that utilize catalytic strategies to synthesize and react S(VI) fluorides. Key mechanistic studies that aim to provide insight toward future catalytic systems are emphasized.

Theranostic Applications Of Sirna Bioconjugates In Cancer Detection And Treatment, Sunil S. Shah

Seton Hall University Dissertations and Theses (ETDs)

Abstract

The emerging field of RNA nanotechnology has led to rapid advances in the applications of RNA in chemical biology, medicinal chemistry, and biotechnology. At the forefront of its utility is the ability to self-assemble multiple siRNAs into nanostructure formulations capable of targeting selected oncogenes and potentiating the gene therapy of malignant tumors. Self-assembled siRNA integrates multiple siRNAs within a single molecular platform for silencing multiple oncogenic mRNA targets with high precision and efficacy to potentially induce cancer cell apoptosis through the RNA interference (RNAi) pathway. Furthermore, the conjugation of siRNA self-assemblies with bio-active probes results in multi-functional theranostic (therapy+diagnostic) …

Advancing The Preclinical Development Of Secondary Metabolites From Cacospongia Mycofijiensis For The Treatment Of Cancer, Joseph Morris

Natural Sciences and Mathematics | Biological Sciences Master's Theses

The marine sponge Cacospongia mycofijiensis from the Indo-Pacific has proven to be a source of structurally diverse secondary metabolites that are biologically active against a variety of distinct targets. Current interest in the secondary metabolites of C. mycofijiensis largely stems from a) their potent and preferential cytotoxicity for cancer cell lines versus normal cells, making many of them promising leads as cancer therapeutics and b) the novel mechanisms of action responsible for their impressive cytotoxicity. However, limited compound availability has resulted in a paucity of studies aimed at advancing the preclinical development of these secondary metabolites from C. mycofijiensis for …

Reeling In New Antibiotics: Synthesis And Antimicrobial Susceptibility Testing Of Zinc-Binding Clavanins From Styela Clava (Sea Squirt), Eduardo Badillo-Colberg

Honors Scholar Theses

Clavanins have been a quite rarely studied antimicrobial peptide (AMP) family. Though the data in the few studies published on the matter and in theoretical experimental data presented by the Wang lab in their peptide library creation [14], in that the members of this family could potentially be quite effective novel antimicrobial candidates. Among those that have been targets of studies, Clavanin A has been at the forefront of this endeavor of finding effective novel antimicrobial peptides[14]. In these aforementioned studies, Clavanin A has been shown to be quite effective against many different bacterial strains, which begs the question as …

Development Of High Throughput Assays For Identification And Evaluation Of Small Molecule Inhibitors Of Microrna-31 Expression, Jackline A. Onyango

Masters Theses

Dysregulated expression of miRNAs has been linked to numerous cancers. On the other hand, miRNAs are potential drug targets due to the ability of their precursor molecules to fold into ligand binding structures. Small-molecule modulators of miRNAs offers opportunity for the development of new therapeutic agents and tools to further probe the mechanisms of miRNA functions. To facilitate the identification of miRNA modulators, the appropriate screening systems are needed, which would be adaptable for high-throughput applications, and allow for quantitative measurements. In this text, we present a molecular beacon-based assay to identify molecules that inhibit miRNA-31 processing by Dicer and …

Synthesis Of Bulky And Polar Galactonoamidines For The Inhibition Of The Human Α-Galactosidase, Ifedi Orizu

Graduate Theses and Dissertations

Glycosidases are amongst the most abundant enzymes in nature. This is due to their role in the degradation of carbohydrates which are the major source of carbon or earth. The absence or malfunction of glycosidases is implicated in numerous diseases such as cancers, diabetes, and lysosomal storage disorders, which make them important drug targets for study in medicinal chemistry. The seminal work by Pauling and Wolfenden showed that enzymes bind to their substrate at the transition state with very strong affinity. Wolfenden estimated the dissociation constant to be around 10-22M. This encouraged the design of glycosidase inhibitors which mimicked one …

Theranostic Nanoparticles Folic Acid-Carbon Dots-Drug(S) For Cancer, Godwin Kweku Babanyinah

Electronic Theses and Dissertations

This study aims to prepare theranostic nanoparticles (NPs) that are expected to increase cancer diagnostics and therapeutic efficacy. We prepared the NPs constituting carbon dots (CDs) as an imaging agent, folic acid as a targeting agent, doxorubicin (DOX), or gemcitabine (GEM) as chemotherapy agents. The NPs include noncovalent FA-CDs-DOX, covalent CDs-FA-DOX, and covalent FA-CDs-GEM. Through ultraviolet-visible spectroscopy, fluorescence spectroscopy, and Fourier transform-infrared spectroscopy, the fabrication of these NPs was confirmed. It was discovered that the high drug loading efficiency is the noncovalent series while the high drug loading capacity is the covalent series The in-vitro pH-dependent drug release data indicate …

Biochemical Characterization Of Small Molecule Inhibitor Binding On A Ras Related Gtpase And Its Effector Interactions, Djamali Muhoza

Graduate Theses and Dissertations

The Ras superfamily of GTPases has 167 proteins that are involved in various cellular processes such as proliferation, transformation, migration, and inhibition of cell death. Mutations, abnormal expression, and function of these proteins are observed in many diseases, including several forms of cancer. Even though these GTPases were among the first discovered oncogenes, no successful Ras drug candidate has successfully passed clinical trials. Drugs targeting these proteins have failed mainly because of the complexity of their regulation, their high affinity to GTP, and their structure’s dynamic nature. Recently, novel promising targeting approaches have renewed interest in the Ras drug discovery …

Structure Formation And Coupling Reactions Of Hexaphenylbenzene And Its Brominated Analog, Jacob D. Teeter, Paulo S. Costa, Christoph Dobner, Mamun Sarker, Alexander Sinitskii, A Enders

Department of Chemistry: Faculty Publications

The on-surface coupling of the prototypical precursor molecule for graphene nanoribbon synthesis, 6,11-dibromo-1,2,3,4-tetraphenyltriphenylene (C₄₂Br₂H₂₆, TPTP), and its non-brominated analog hexaphenylbenzene (C₄₂H₃₀, HPB), was investigated on coinage metal substrates as a function of thermal treatment. For HPB, which forms non-covalent 2D monolayers at room temperature, a thermally induced transition of the monolayer’s structure could be achieved by moderate annealing, which is likely driven by π-bond formation. It is found that the dibrominated carbon positions of TPTP do not guide the coupling if the growth occurs on a substrate at temperatures that …

Data For "Subtype-Selective Positive Modulation Of Sk Channels Depends On The Ha/Hb Helices", Miao Zhang, Meng Cui

Pharmacy Faculty Data Sets

In the activated state of small-conductance Ca²⁺-activated potassium (SK) channels, calmodulin interacts with the HA/HB helices and the S4-S5 linker. CyPPA potentiates SK2a and SK3 channel activity but not the SK1 and IK subtypes. Here, we report that the subtype-selectivity of CyPPA relies on the HA/HB helices. Mutating residues in the HA (V420) and HB (K467) helices of SK2a channels to their equivalent residues in IK channels diminished the potency of CyPPA. CyPPA elicited prominent responses on mutant IK channels with an arginine residue in the HB helix substituted for its equivalent lysine residue in the SK2a channels …

Effective Microwave-Assisted Approach To 1,2,3-Triazolobenzodiazepinones Via Tandem Ugi Reaction/Catalyst-Free Intramolecular Azide–Alkyne Cycloaddition, Maryna O. Mazur, Oleksii S. Zhelavskyi, Eugene M. Zviagin, Svitlana V. Shishkina, Vladimir I. Musatov, Maksim A. Kolosov, Elena H. Shvets, Anna Yu. Andryushchenko, Valentyn A. Chebanov

Department of Chemistry: Faculty Publications

A novel catalyst-free synthetic approach to 1,2,3-triazolobenzodiazepinones has been developed and optimized. The Ugi reaction of 2-azidobenzaldehyde, various amines, isocyanides, and acids followed by microwave-assisted intramolecular azide–alkyne cycloaddition (IAAC) gave a series of target heterocyclic compounds in moderate to excellent yields. Surprisingly, the normally required ruthenium-based catalysts were found to not affect the IAAC, only making isolation of the target compounds harder while the microwave-assisted catalyst-free conditions were effective for both terminal and non-terminal alkynes

Sulfur Anions: Comments Upon Structure, Charles A. Kingsbury

Department of Chemistry: Faculty Publications

This work emphasizes the need for solvent simulation as well as a counterion in calculations concerning anions, although optimization may be difficult. Solvent and counterion both play a large role in conformation of the ion. Part of the reason for the success of sulfur anions in chemical reactions may be the ability of sulfone oxygen(s) to coordinate with the counterion (usually lithium). The “solvent” partially dissociates lithium from the carbanion center.

Identifying Receptors For Neuropeptides And Peptide Hormones: Challenges And Recent Progress, Md Shadman Ridwan Abid, Somayeh Mousavi, James W. Checco

Department of Chemistry: Faculty Publications

Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive peptides, the protein receptors that transmit information across the receiving cell membrane are not known, severely limiting these signaling pathways as potential therapeutic targets. Identifying the receptor(s) for a given peptide of interest is complicated by several factors. Most notably, cell-cell signaling peptides are generated through dynamic biosynthetic pathways, can act on many different families of receptor proteins, and can participate in complex ligand-receptor interactions that extend beyond a simple one-to-one archetype. Here, we discuss recent methodological advances …

Using Molecular Dynamics Simulations To Understand Receptor-Complex Communication And Signaling, Hannah Margaret Hoag

Theses and Dissertations

The overarching purpose of this document is to use Computer-aided drug design and Molecular dynamic simulations to better understand elusive drug-receptor interactions, as well as various types of inter-receptor signaling. Chapter One introduces the theory and importance of Computer-aided drug design and the methodology used in both Chapters Two and Three.

Chapter Two uncovers the relationship between the well-studied ABCB1 transporter and a newly identified drug known as Xanthohumol (XN). XN is compared to a commonly used drug, Doxorubicin (DOX), in this chapter. If the ABCB1 transporter can be properly inhibited, cancer-fighting drugs will be able to stay within the …

Label‑Free Spectral Imaging To Study Drug Distribution And Metabolism In Single Living Cells, Qamar Alshammari, Rajasekharreddy Pala, Nir Katzir, Surya M. Nauli

Pharmacy Faculty Articles and Research

During drug development, evaluation of drug and its metabolite is an essential process to understand drug activity, stability, toxicity and distribution. Liquid chromatography (LC) coupled with mass spectrometry (MS) has become the standard analytical tool for screening and identifying drug metabolites. Unlike LC/MS approach requiring liquifying the biological samples, we showed that spectral imaging (or spectral microscopy) could provide high-resolution images of doxorubicin (dox) and its metabolite doxorubicinol (dox’ol) in single living cells. Using this new method, we performed measurements without destroying the biological samples. We calculated the rate constant of dox translocating from extracellular moiety into the cell and …

The Mechanism Of Β-N-Methylamino-L-Alanine Inhibition Of Trna Aminoacylation And Its Impact On Misincorporation, Nien-Ching Han, Tammy J. Bullwinkle, Kaeli F. Loeb, Kym F. Faull, Kyle Mohler, Jesse Rinehart, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

β-N-methylamino-l-alanine (BMAA) is a nonproteinogenic amino acid that has been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). BMAA has been found in human protein extracts; however, the mechanism by which it enters the proteome is still unclear. It has been suggested that BMAA is misincorporated at serine codons during protein synthesis, but direct evidence of its cotranslational incorporation is currently lacking. Here, using LC-MS–purified BMAA and several biochemical assays, we sought to determine whether any aminoacyl-tRNA synthetase (aaRS) utilizes BMAA as a substrate for aminoacylation. Despite BMAA's previously predicted misincorporation at serine …

Synthesis And Cytotoxicity Of Trisubstituted Imidazoles, Venkata Agasthya Kasibotla

Theses and Dissertations

Aza heterocyclic compounds are an important class of organic compounds that play a major role in medicinal chemistry. Majority of the heterocyclic motifs such as imidazoles, triazoles, piperazines etc. act as building blocks for synthesizing active pharmaceutical ingredients. Several pharmaceutical drugs include these motifs due to their varying physicochemical properties, which enable them to exhibit wide range of pharmacological activities ranging from anti-fungal, anti-neoplastic, anti-helmintic, anti-microbial etc. Owing to their electron rich ring system, imidazole and piperazine based motifs have become an attractive target for design and development of novel chemical structures as new drugs. In the current study, we …