Other Chemicals and Drugs Commons^™

Killing Cancer: Manipulating Hydrophobic Vanadium Complexes To Improve Anti-Cancer Activity, Levi Ausherman, Debbie C. Crans, Peter A. Lay, Maggi Braasch-Turi

SACAD: John Heinrichs Scholarly and Creative Activity Days

Hydrophobic vanadium complexes have recently shown improved anti-cancer activities compared to cisplatin. The hydrophobicity and anti-proliferative activity of [VO(Hshed)(dtb)] ([Hshed= N-(salicylideneaminato)-N’-(2-hydroxyethyl)-1,2-ethanediamine and dtb= 3,5-di(tert-butyl)catechol)]) have inspired the development of a library of hydrophobic vanadium complexes. Increasing the steric bulk of the catechol ligand has been shown to have a direct impact on hydrophobicity and anti-proliferative activities. Currently at Fort Hays State University, the Braasch-Turi group is synthesizing VO(HSHED)(dtb) to build up material to support the chemical analysis and biological assay performed by our collaborators at Colorado State University and the University of Sydney, Australia, respectively. In the future, we plan …

Accurate Characterization Of Binding Kinetics And Allosteric Mechanisms For The Hsp90 Chaperone Inhibitors Using Ai-Augmented Integrative Biophysical Studies, Chao Xu, Xianglei Zhang, Lianghao Zhao, Gennady M. Verkhivker, Fang Bai

Mathematics, Physics, and Computer Science Faculty Articles and Research

The binding kinetics of drugs to their targets are gradually being recognized as a crucial indicator of the efficacy of drugs in vivo, leading to the development of various computational methods for predicting the binding kinetics in recent years. However, compared with the prediction of binding affinity, the underlying structure and dynamic determinants of binding kinetics are more complicated. Efficient and accurate methods for predicting binding kinetics are still lacking. In this study, quantitative structure–kinetics relationship (QSKR) models were developed using 132 inhibitors targeting the ATP binding domain of heat shock protein 90α (HSP90α) to predict the dissociation rate …

Reactive Chemistries For Protein Labeling, Degradation, And Stimuli Responsive Delivery, Myrat Kurbanov

Doctoral Dissertations

Reactive chemistries for protein chemical modification play an instrumental role in chemical biology, proteomics, and therapeutics. Depending on the application, the selectivity of these modifications can range from precise modification of an amino acid sequence by genetic manipulation of protein expression machinery to a stochastic modification of lysine residues on the protein surface. Ligand-Directed (LD) chemistry is one of the few methods for targeted modification of endogenous proteins without genetic engineering. However, current LD strategies are limited by stringent amino acid selectivity. To bridge this gap, this thesis focuses on the development of highly reactive LD Triggerable Michael Acceptors (LD-TMAcs) …

Photodynamic Therapy Agents: The Power Of Mjöllnir To Eradicate Cancer, Sidney M. Hopper

Honors College Theses

After its discovery back in the 1900s, photosensitizers became a critical study for potential treatments and cures for medical issues, including cancer. It was discovered that porphyrins appeared to target and accumulate in proliferating cells, and to reach the cells, a certain wavelength of light with maximum absorbance associated with the porphyrin was necessary to achieve cell death. Photodynamic therapy involves making use of porphyrins or metalloporphyrins as activators when exposed to such light. When activated, these compounds generate reactive oxygen species (ROS), such as HO- or O2-, which can react with nucleic acids found in DNA and RNA. In …

“Translation Of Hdac6 Pet Imaging Using [18f]Ekz-001 – Cgmp Production And Measurement Of Hdac6 Target Occupancy In Nhps” – A Review, Dania Rahal

Chemistry & Biochemistry Undergraduate Honors Theses

The inhibition of histone deacetylase 6 (HDAC6) has been reported to alleviate the effects of neurodegenerative diseases such as Alzheimer’s disease. The brain-penetrant PET radioligand [¹⁸F]EKZ-001 has high affinity and selectivity towards HDAC6 and therefore suggests great promise in therapeutic treatment studies and development for neurodegenerative diseases. “Translation of HDAC6 PET imaging using [¹⁸F]EKZ-001 – cGMP production and measurement of HDAC6 target occupancy in NHPs” has achieved an effective, fully automated method of producing [¹⁸F]EKZ-001 in compliance with current good manufacturing practices (cGMP) to support the translation of [¹⁸F]EKZ-001 PET for …

Structural And Computational Studies Of The Sars-Cov-2 Spike Protein Binding Mechanisms With Nanobodies: From Structure And Dynamics To Avidity-Driven Nanobody Engineering, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …

Design And Synthesis Of Small Molecular Probes For Cns And Kidney Disorders, Swagat H. Sharma

Theses & Dissertations

The G protein regulated inwardly rectifying potassium channels (GIRK) are a family of inwardly rectifying potassium channels and are key effectors in signaling pathways. GIRK 1/2 channel subunit, predominantly found in the brain, is involved pathophysiology of various neurological disorders including, but not limited to, epilepsy, anxiety, Parkinson's, pain, reward, and addiction. Previously, our laboratory had identified a series of urea containing molecules as GIRK1/2 preferring activators. Unfortunately, the urea series suffers from significant PK liabilities (solubility, brain penetration and high clearance). The chapter 1 of the dissertation describes our efforts in developing three new series of activators with improved …

Aptamer-Based Voltammetric Biosensing For The Detection Of Codeine And Fentanyl In Sweat And Saliva, Rosa Lashantez Cromartie

FIU Electronic Theses and Dissertations

Despite the many governmental and medicinal restrictions created to combat the opioid epidemic in the United States, opioid abuse and overdose rates continue to rise. The development of an aptamer-based voltammetric sensor and biosensor is described in this dissertation. The aim was to develop a low-cost, sensitive, and specific aptamer-based sensor for on-site, label-free determination of codeine and fentanyl in biological fluids. To do this, the surfaces of screen-printed carbon electrodes (SPCE) were modified with gold nanoparticles (AuNPs), followed by the addition of single-stranded DNA aptamers. These were covalently bound to the electrode surface. Operations of the sensors were collected …

Atomistic Simulations And In Silico Mutational Profiling Of Protein Stability And Binding In The Sars-Cov-2 Spike Protein Complexes With Nanobodies: Molecular Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Deniz Yasar Oztas, Grace Gupta

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structure-functional studies have recently revealed a spectrum of diverse high-affinity nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this study, we combine atomistic simulations with the ensemble-based mutational profiling of binding for the SARS-CoV-2 S-RBD complexes with a wide range of nanobodies to identify dynamic and binding affinity fingerprints and characterize the energetic determinants of nanobody-escaping mutations. Using an in silico mutational profiling approach for probing the protein stability and binding, we examine dynamics and energetics of the SARS-CoV-2 complexes with single nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E + …

Molecular Dynamics Simulations Of Self-Assemblies In Nature And Nanotechnology, Phu Khanh Tang

Dissertations, Theses, and Capstone Projects

Nature usually divides complex systems into smaller building blocks specializing in a few tasks since one entity cannot achieve everything. Therefore, self-assembly is a robust tool exploited by Nature to build hierarchical systems that accomplish unique functions. The cell membrane distinguishes itself as an example of Nature’s self-assembly, defining and protecting the cell. By mimicking Nature’s designs using synthetically designed self-assemblies, researchers with advanced nanotechnological comprehension can manipulate these synthetic self-assemblies to improve many aspects of modern medicine and materials science. Understanding the competing underlying molecular interactions in self-assembly is always of interest to the academic scientific community and industry. …

Ganglioside Alters Phospholipase Trafficking, Inhibits Nf-Κb Assembly, And Protects Tight Junction Integrity, John J. Miklavcic, Qun Li, Jordan Skolnick, Alan B. R. Thomson, Vera C. Mazurak, Michael Tom Clandinin

Food Science Faculty Articles and Research

Background and Aims: Dietary gangliosides are present in human milk and consumed in low amounts from organ meats. Clinical and animal studies indicate that dietary gangliosides attenuate signaling processes that are a hallmark of inflammatory bowel disease (IBD). Gangliosides decrease pro-inflammatory markers, improve intestinal permeability, and reduce symptoms characteristic in patients with IBD. The objective of this study was to examine mechanisms by which dietary gangliosides exert beneficial effects on intestinal health.

Methods: Studies were conducted in vitro using CaCo-2 intestinal epithelial cells. Gangliosides were extracted from milk powder and incubated with differentiated CaCo-2 cells after exposure to pro-inflammatory stimuli. …

Development Of A Rapid Drug Detection Method For Insects Using Paper Spray Ionization Mass Spectrometry (Psi-Ms), Alexandria Plyler

Undergraduate Research and Scholarship Symposium

Insects have the ability to reflect the chemical environment that they have developed in. Thus, necrogenous insects can reflect the chemical environment of cadavers they have fed on. Forensic scientists can potentially utilize insect larvae as an alternate biological matrix to detect drugs in cadavers that are skeletonized, burned, or otherwise badly damaged. Analysis of insects using paper spray ionization mass spectrometry (PSI-MS), an analytical method requiring little to no sample preparation, could prove a rapid, cost-effective, and non-destructive alternative form of toxicological analysis. Traditional tissue analysis via GC and LC-MS often require lengthy sample preparation, use expensive reagents, and …

Capsaicin Is A Negative Allosteric Modulator Of The 5-Ht3 Receptor, Eslam El Nebrisi, Tatiana Prytkova, Dietrich Ernst Lorke, Luke Howarth, Asma Hassan Alzaabi, Keun-Hang Susan Yang, Frank Christopher Howarth, Murat Oz

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In this study, effects of capsaicin, an active ingredient of the capsicum plant, were investigated on human 5-hydroxytryptamine type 3 (5-HT₃) receptors. Capsaicin reversibly inhibited serotonin (5-HT)-induced currents recorded by two-electrode voltage clamp method in Xenopus oocytes. The inhibition was time- and concentration-dependent with an IC₅₀ = 62 μM. The effect of capsaicin was not altered in the presence of capsazepine, and by intracellular BAPTA injections or trans-membrane potential changes. In radio-ligand binding studies, capsaicin did not change the specific binding of the 5-HT₃ antagonist [³H]GR65630, indicating that it is a noncompetitive inhibitor of …

The Histone Deacetylase Inhibitor Largazole: A Potential Chemotherapeutic Agent, Hannah Lynn Carson

Honors Theses

Histone deacetylase enzymes are known for their inherent activity as epigenetic modifiers. Although, they have become recognized for their role in cancer progression and other diseases. But also, histone deacetylases have other non-histone targets, for example, microtubules, which play important roles in cancer metastasis, apoptosis, and replication. With histone deacetylase inhibitors (HDACi), our research explored HDACi effects on breast cancer cell lines. The overall goal was to understand the potential of largazole, a class one histone deacetylase inhibitor on breast cancer cell lines. The research consisted of two parts: sulforhodamine B (SRB) viability assays under hypoxic and normoxic conditions. The …

Surface-Enhanced Raman Spectroscopy For Cocaine Detection, Kiersten Jo Mead

Chemistry

The detection of drugs of abuse using Raman spectroscopy is of particular interest to forensic researchers at the moment. Raman spectroscopy is highly specific, fast, non-destructive, and can be adapted for in-situ measurements, making it the ideal forensic technique. Researchers working under the guidance of Doctor Igor Lednev have been able to use UV resonance Raman spectroscopy to detect cocaine in oral fluid without the need for sample pretreatment. They were however unable to detect the cocaine at forensically relevant levels. To overcome this limitation, surface-enhanced Raman spectroscopy (SERS) was used in this proof of concept study for the detection …

Antifungal Defense Molecules From Bacterial Symbionts Of North American Trachymyrmex Ants, Georgia Scherer

CMC Senior Theses

Defensive symbioses, in which microbes provide molecular defenses for an animal host, hold great potential as untapped sources of therapeutically useful antibiotics. Fungus-growing ants use antifungal defenses from bacterial symbionts to suppress pathogenic fungi in their nests. Preliminary chemical investigations of symbiotic bacteria from this large family of ants have uncovered novel antifungal molecules with therapeutic potential, such as dentigerumycin and selvamicin.

In this study, the bacterial symbionts of North American Trachymyrmex fungus-growing ants are investigated for antifungal molecules. Plate-based bioassays using ecologically-relevant fungal pathogens confirmed that these bacteria have antifungal activity. In order to purify and identify the antifungal …

E-Cigarette Chemistry And Analytical Detection, Robert M. Strongin

Chemistry Faculty Publications and Presentations

The study of e-cigarette aerosol properties can inform public health while longer-term epidemiological investigations are ongoing. The determination of aerosol levels of known toxins, as well as of molecules with unknown inhalation toxicity profiles, affords specific information for estimating the risks of e-cigarettes and for uncovering areas that should be prioritized for further investigation.

Microgel Core/Shell Architectures As Targeted Agents For Fibrinolysis, Purva Kodlekere, L. Andrew Lyon

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

We demonstrate the utility of microgel core/shell structures conjugated to fibrin-specific peptides as fibrinolytic agents. Poly(N-isopropylmethacrylamide) (pNIPMAm) based microgels conjugated to the peptide GPRPFPAC (GPRP) were observed to bring about fibrin clot erosion, merely through exploitation of the dynamic nature of the clots. These results suggest the potential utility of peptide–microgel hybrids in clot disruption and clotting modulation.

5-Ht2b Receptor-Mediated Cardiac Valvulopathy, Pallavi Nistala

Theses and Dissertations

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens …

Fabrication And Modification Of Titania Nanotube Arrays For Harvesting Solar Energy And Drug Delivery Applications, Ahmed El Ruby Abdel Rahman Mohamed

Electronic Thesis and Dissertation Repository

The fast diminishing of fossil fuels in the near future, as well as the global warming caused by increasing greenhouse gases have motivated the urgent quest to develop advanced materials as cost-effective photoanodes for solar light harvesting and many other photocatalytic applications. Recently, titania nanotube arrays (TNTAs) fabricated by anodization process has attracted great interest due to their excellent properties such as: high surface area, vertically oriented, highly organized, one-dimensional, nanotubular structure, photoactivity, chemical stability and biocompatibility. This unique combination of excellent properties makes TNTAs an excellent photoanode for solar light harvesting. However, the relatively wide band gap energy of …

Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions ofmenthol. There has been new evidence demonstrating thatmenthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at …

Detection Of Cathinone And Mephedrone In Plasma By Lc-Ms/Ms Using Standard Addition Quantification Technique, Theron W. Ng-A-Qui

Student Theses

Designer drugs are structural analogs of Drug Enforcement Agency (DEA) Schedule I and II substances. They are synthesized to mimic the effects of illegal drugs of abuse and to bypass the provisions of drug regulations. Despite the increased availability of designer drugs, few studies have focused on specific analytical extraction techniques for their detection and quantification in biological samples. Solid phase extraction (SPE) is the most commonly used technique for sample preparation. The purpose of this study is to evaluate the extraction efficiency of the various SPE columns with different sorbent materials for two designer drugs, cathinone and mephedrone in …

One-Pot Syntheses And Characterizations Of “Click-Able” Polyester Polymers For Potential Biomedical Applications, James F. Beach Ii

Electronic Theses & Dissertations

In this study, a synthetic polyester polymer was designed using polyethylene glycol, sorbitol, glutaric acid and 4-pentynoic acid as monomers. The synthesis was carried out using standard melt polymerization technique and catalyzed by Novozyme-435, an enzyme suitable for polyesterification of biocompatible compounds. The progress of the reaction was monitored with respect to time and vacuum exposure, with samples being subjected to standard characterization protocols. Polymers with high molecular weight and water solubility were chosen for further modification into folate-functionalized polymeric nanoparticles for targeted drug delivery to cancer cells. This was achieved by employing a solvent diffusion method, wherein the polymer …

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: …

A Diversity-Oriented Synthesis Approach To Functionalized Azaheterocycles Using Cyclic Alpha-Halo Eneformamides, Spencer A. Langevin

All Master's Theses

Functionalized piperidines, azepanes, azamacrocycles, morpholines, and thiomorpholines are common structural motifs found in a wide range of pharmaceuticals such as carmegliptine, levofloxacin, thioridazine, claviciptic acid, and azithomycin. As a result, there is a strong desire to construct highly functionalized nitrogen-bearing ring scaffolds in order to construct a wide range of drug possibilities. There are several non-modular and step-uneconomical synthetic methods used in the construction of these aforementioned motifs such as ring closing metathesis, ring expansions, and intramolecular reductive amination. In this research, we present a step-economical, cost-effective, scalable, and diversity-oriented synthesis approach to highly functionalized N-heterocycles through the intermediacy of …

Multipurpose Tenofovir Disoproxil Fumarate Electrospun Fibers For The Prevention Of Hiv-1 And Hsv-2 Infections., Kevin Tyo

Electronic Theses and Dissertations

Sexually transmitted infections affect hundreds of millions of worldwide. Both human immunodeficiency virus (HIV-1 and -2) and herpes simplex virus-2 (HSV-2) remain incurable, urging the development of new prevention strategies. While current prophylactic technologies are dependent on strict user adherence to achieve efficacy, there is a dearth of delivery vehicles that provide discreet and convenient administration, combined with prolonged-delivery of active agents. To address these needs, we created electrospun fibers (EFs) comprised of FDA-approved polymers, poly(lactic-co-glycolic acid) (PLGA) and poly(DL-lactide-co-ε-caprolactone) (PLCL), to provide sustained-release and in vitro protection against HIV-1 and HSV-2. PLGA and PLCL EFs, incorporating the antiretroviral, tenofovir …

Comparing The Quantitation Of Opiates From Possible Drug Overdose Cases Using Results Of Blood Analysis And Liver Analysis, Lee Ann Garozzo

Forensic Science Theses

Currently the quantitation of opiates at the Erie County Medical Examiner’s Office Toxicology Laboratory is conducted through whole blood analysis. The objective of this thesis project was to determine if the analysis of opiates could be conducted through liver analysis, and if the analysis of opiates would provide a more accurate quantitation compared to the blood analysis. The quantitation of opiates was conducted from the livers of sixty-four possible overdose cases that were brought into the Erie County Medical Examiner’s Office between 2013 and 2015. Results showed that the opiate drugs could successfully be quantitated using the liver analysis. Generally …

Interrogating Metabolism In Brain Cancer, Travis Salzillo, Jingzhe Hu, Linda Nguyen, Nicholas Whiting, Jaehyuk Lee, Joseph Weygand, Prasanta Dutta, Shivanand Pudakalakatti, Niki Zacharias Millward, Seth Gammon, Frederick F. Lang, Amy B. Heimberger, Pratip Bhattacharya

Nicholas Whiting

Analysis Of Synthetic Cannabinoids By Direct Analysis In Real Time Quadrupole Time-Of-Flight Mass Spectrometry And Gas Chromatography Quadrupole Time-Of-Flight Mass Spectrometry, Tyler S. Torbet

FIU Electronic Theses and Dissertations

The aim of this study was to investigate the utility of direct analysis in real time quadrupole time-of-flight mass spectrometry and gas chromatography quadrupole time-of-flight mass spectrometry in the analysis of 162 different synthetic cannabinoids. Direct analysis in real time quadrupole time-of-flight mass spectrometry is shown to be a rapid and accurate analytical method for synthetic cannabinoids. Spectra can be generated with less than 1.5 ng of the drug in under a minute and be successfully searched against previously generated ESI-QTOF libraries in most cases (118/130 drugs tested) as well as can also be applied to the identification of synthetic …