Medicinal-Pharmaceutical Chemistry Commons^™

Melanogenesis, Its Regulatory Process, And Insights On Biomedical, Biotechnological, And Pharmacological Potentials Of Melanin As Antiviral Biochemical, Toluwase Hezekiah Fatoki, Omodele Ibraheem, Catherine Joke Adeseko, Boluwatife Lawrence Afolabi, Daniel Uwaremhevho Momodu, David Morakinyo Sanni, Jesupemi Mercy Enibukun, Ibukun Oladejo Ogunyemi, Akinwunmi Oluwaseun Adeoye, Harriet U. Ugboko, Amoge Chidinma Ogu, Abiodun Samuel Oyedele, Adejoju Omodolapo Adedara, Abiodun Joseph Jimoh, Oluwakemi Ruth Ogundana, Oritsetimeyin Eworitse Ebosa

Chemistry Student Research

Melanin is s most widely distributed pigment and is found in bacteria, fungi, plants, and animals. Melanogenesis is under complex regulatory control by multiple agents interacting through pathways activated by hormonal and receptor-dependent and -independent mechanisms. There are about 20 genes that are involved in the biochemical pathway of melanogenesis and its regulation, which include: tyrosinase, microphthalmia-associated transcription factor, melanocortin1 receptor, adenylate cyclase, protein kinase A. Human melanogenesis regulatory proteins such as MAPK1, CREB3, and CREBP, have binary interaction with the protein of herpesvirus, hepatitis C virus, Human immunodeficiency virus type 1, Simian virus 40, and Human adenovirus A and …

Applied Molecular Dynamics: From Targeting Viral Helicases, To Understanding The Interactions Of Cucurbituril Complexes In Ionic Solutions, Bryan Raubenolt

University of New Orleans Theses and Dissertations

Molecular Dynamics simulations are a highly useful tool in helping understand the fundamental interactions present in a variety of chemical systems. The work discussed here illustrates it’s use in determining the conformational dynamics of the Zika and SARS-Cov-2 helicase in a physiological environment, largely in an effort to discover inhibitors capable of rendering the protein inert. Additionally, we show how it can be used to understand paradoxical trends in the anion-induced precipitation of Cucurbituril cavitands.

Viral helicases are motor proteins tasked with unwinding the viral dsRNA, a crucial step in preparing the strand to be translatable by host cells. By …

Design And Synthesis Of Novel No-Drug Hybrid Compound And Green Catalytic Activity Evaluation Of Synthesized Silver Nanoparticles-Halloysite Nanocomposite, Majed Abdullah Bajaber

University of New Orleans Theses and Dissertations

Acetaminophen is a well-known analgesic that can manage pain and reduce fever. SCP-1 is a derivative of acetaminophen that showed significantly reduced hepatotoxicity and nephrotoxicity comparative to acetaminophen. Nitric oxides have been well known to play a key role in a wide variety of physiological and pathophysiological important processes. It was therefore of interest to synthesize a nitric oxide donor linked to SCP-1 that could have enhanced analgesic and antipyretic activity. A furoxan CAS 1609 as NO-donor was synthesized and linked to SCP-1 successfully. The furoxan CAS 1609 was initially synthesized from tetronic acid to give 1,2- dioxime in 86 …

Nuclear-Targeted Gold Nanoparticles Enhance The Effects Of Radiation Therapy With And Without Liposomal Delivery, Maureen Aliru

Dissertations & Theses (Open Access)

Less that 10% of pancreatic cancer patients are eligible for curative resection, and clinical trials evaluating chemoradiation in locally advanced patients with unresectable disease have been largely disappointing. New and creative therapeutic approaches are needed to address the unment need for treatment options. The objective of this thesis is to advance radiosensitization of treatment-resistant densely desmoplastic pancreatic cancer using nanoparticles to surmount biological barriers to effective particle distribution for DNA-targeting.

Clinical translation of radiosensitizing nanoparticles has stalled owing to technical challenges. Current strategies to use AuNPs for radiosensitization require large quantities of gold, kilovoltage x-rays, immediate irradiation after intravenous administration, …

Coevolution, Dynamics And Allostery Conspire In Shaping Cooperative Binding And Signal Transmission Of The Sars-Cov-2 Spike Protein With Human Angiotensin-Converting Enzyme 2, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of …

Synthesis, In Vitro, And In Vivo Evaluation Of Novel N-Phenylindazolyl Diarylureas As Potential Anti-Cancer Agents., Lucas N Solano, Grady L Nelson, Conor T Ronayne, Shirisha Jonnalagadda, Sravan K Jonnalagadda, Kaija Kottke, Robert Chitren, Joseph L Johnson, Manoj K Pandey, Subash C. Jonnalagadda, Venkatram R Mereddy

Faculty Scholarship for the College of Science & Mathematics

Novel N-phenylindazole based diarylureas have been designed, synthesized and evaluated as potential anticancer agents. In vitro cell viability studies of these derivatives illustrate good potency with IC50 values in the range of 0.4–50 μM in several cancer cell lines including murine metastatic breast cancer 4T1, murine glioblastoma GL261, human triple negative breast cancer MDA-MB-231, human pancreatic cancer MIAPaCa-2, and human colorectal cancer cell line WiDr. The ester group in the lead compound 8i was modified to incorporate amino-amides to increase solubility and stability while retaining biological activity. Further in vitro studies reveal that lead candidates inhibit tube length in HUVEC …

Design And Synthesis Of Core–Shell Microgels With One‐Step Clickable Crosslinked Cores And Ultralow Crosslinked Shells, Molla R. Islam, Chelsea Nguy, Sanika Pandit, L. Andrew Lyon

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The present study is conducted to explore the engineering of core–shell microgels such that the core can be rapidly labeled with a variety of fluorophores, while the shell retains the softness needed in specific biomedical applications. Azide containing crosslinked core particles based on a crosslinked poly(N‐isopropylacrylamide) particle, using a one‐pot, multistep polymerization is synthesized. A core–shell microgel is then synthesized by growing a crosslinker‐free poly(N‐isopropylacrylamide)‐co‐acrylic acid (ULC10AAc) shell through a two‐step seed and feed polymerization. A simple “click” reaction between the azide present on the core and dibenzocyclooctyne containing fluorophores to make dyed core–shell …

Isolation, Structure Elucidation, And Synthesis Of Natural Products From Marine Cyanobacteria, Keren Solomon

Electronic Theses and Dissertations

This thesis describes the isolation, structure elucidation, and synthesis of natural products from marine cyanobacteria. A crude extract from a cyanobacterium collected in Curacao showed selective affinity for the dopamine D₅ receptor in a screen against a panel of CNS receptors. Due to the high similarity of the D₅ and D₁ receptor, to date there are no known ligands that differentiate them. Attempts to purify the compound responsible for this affinity led to the isolation of the known compound caylobolide A. A second extract from a cyanobacterium collected in Panama underwent bioassay-guided fractionation and yielded the novel …

Machine Learning Approaches For Improving Prediction Performance Of Structure-Activity Relationship Models, Gabriel Idakwo

Dissertations

In silico bioactivity prediction studies are designed to complement in vivo and in vitro efforts to assess the activity and properties of small molecules. In silico methods such as Quantitative Structure-Activity/Property Relationship (QSAR) are used to correlate the structure of a molecule to its biological property in drug design and toxicological studies. In this body of work, I started with two in-depth reviews into the application of machine learning based approaches and feature reduction methods to QSAR, and then investigated solutions to three common challenges faced in machine learning based QSAR studies.

First, to improve the prediction accuracy of learning …

Directed Evolution Of Macrocyclic Peptides For Inhibition Of Autophagy, Joshua Gray

Dissertations & Theses (Open Access)

In recent decades it has become increasingly clear that induction of autophagy plays an important role in the development of treatment resistance and dormancy in many cancer types. Chloroquine (CQ) and hydroxychloroquine (HCQ), two autophagy inhibitors in clinical trials, suffer from poor pharmacokinetics and high toxicity at therapeutic dosages. This has prompted intense interest in the development of targeted autophagy inhibitors to re-sensitize disease to treatment with minimal impact on normal tissue. We utilized Scanning Unnatural Protease Resistant (SUPR) mRNA display to develop macrocyclic peptides targeting the autophagy protein LC3. The resulting peptides bound LC3A and LC3B—two essential components of …

Investigating Chitosan Modified With Triethylammonium Butanamide And Triethylphosphonium Butanamide As Non-Viral Gene Delivery Vectors By Examining Cytotoxicity And Transfection Efficiency, Deborah C. Ehie

MSU Graduate Theses

Gene therapy is a very challenging field, especially with new emerging genetic disorders. Chitosan (CS), due to chitosan’s flexibility, biocompatibility, and biodegradability, has been of interest in the world of gene therapy especially as researchers are gravitating towards non-viral vectors due to the problems caused by viral vectors. Nevertheless, there are still issues regarding solubility, cellular uptake of cargos being transported in vitro or in vivo, increased cytotoxicity levels, as well as many other things that prevent chitosan from being an efficient gene delivery agent. Here I present five derivatives of chitosan, which were all modified with either triethylphosphonium …

Visualization Without Vision – How Blind And Visually Impaired Students And Researchers Engage With Molecular Structures, Croix J. Laconsay, Henry B. Wedler, Dean J. Tantillo

Journal of Science Education for Students with Disabilities

This article examines the tools and techniques currently available that enable blind and visually impaired (BVI) individuals to visualize three-dimensional objects used in learning chemistry concepts. How BVI individuals engage with and visualize molecular structure is discussed and recent tactile (or haptic) and auditory methods for visualization of various chemistry concepts are summarized. Remaining challenges for chemistry education researchers are described with the aim of highlighting the potential value of educational research in further enabling BVI students to pursue careers in science, technology, engineering, and mathematics (STEM) fields.

Chemical Manipulation Of Macrophages: Nanomaterial And Molecular Approaches, Joseph Hardie

Doctoral Dissertations

Macrophages, phagocytic cells of the innate immune system, are the body’s first line of defense against pathogens and are responsible for tissue maintenance. Macrophages are capable of sensing and internalizing external stimuli, and in response change their morphology and phenotype accordingly. Because macrophages are integral to immune function and tissue maintenance, dysregulation of macrophage behavior is associated with a range of diseases including infections, cancer, autoimmune disorders, atherosclerosis, and more. Because of the implications of macrophage failure, there is interest in creating new materials to manipulate macrophage behavior for a therapeutic effect. In this thesis, I describe the application of …

Gama-Lactams And The Reformatsky Reaction: New Tricks For Old Chemistry, Dylan Dupont

Honors Theses

DUPONT, DYLAN. An Alternative Synthetic Pathway to γ-Lactam Compounds

Through the Application of Novel Reformatsky-Type Chemistry. Department

of Chemistry, June 2020

ADVISOR: James C. Adrian Jr. Ph.D.

It is the intent of the present report to relate the results of our attempt to elucidate and optimize a novel preparation of γ-lactam compounds. To achieve this end, it is proposed that the use of novel Reformatsky-type chemistry may provide a viable means. Generally, it has herein been validated that employment of α-amino ketones in traditional Reformatsky chemistry will form the traditional Reformatsky ester-adduct, and that this adduct is capable of spontaneously …

Sufex Activation With Ca(Ntf2)2: A Unified Strategy To Access Sulfamides, Sulfamates, And Sulfonamides From S(Vi) Fluorides, Nicholas Ball, Subham Mahapatra, Cristian P. Woroch, Todd W. Butler, Sabrina N. Carneiro, Sabrina C. Kwan, Samuel R. Khasnavis, Junha Gu, Jason K. Dutra, Beth C. Vetelino, Justin Bellenger, Christopher W. Am Ende

Pomona Faculty Publications and Research

A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

Synthesis Of The Natural Alkaloids Angustureine, Cuspareine, Galipeine, Galipinine Using Α-Aminocycloalkyl Copper Reagents, Zane Bertoli

Master of Science in Chemical Sciences Theses

Tetrahydroquinolines (THQs) are a group of N-heterocyclic molecules derived from natural sources. They show a wide range of interesting biological activity and have been the basis for a variety of different medications including antibacterial and antiparasitic drugs. The Hancock alkaloids, Galipinine, Galipeine, Cuspareine and Angustureine, are natural 1,2,3,4- tetrahydroquinoline compounds that are found in the South American Angostura tree. Extracts containing these alkaloids have been used to treat fever, dysentery and other ailments. Interestingly, These compounds have shows in vitro antimalarial activity. However, it does not appear in the literature that they have been evaluated for their potential antibiotic activity. …

Synthesis And Evaluation Of Novel Biologically Active Compounds, Madhurima Das

University of New Orleans Theses and Dissertations

SCP-1, a potent derivative of acetaminophen, exhibits significantly diminished hepatotoxicity and nephrotoxicity relative to acetaminophen and nitrate ester derivatives of acetaminophen. It was therefore of interest to explore the development of nitric oxide donor analogs of SCP-1 to identify compounds that could have enhanced analgesic and/or antipyretic activity while taking advantage of the very low liver and kidney toxicity inherent to SCP-1. In this project, a series of nitrate ester analogues of the SCP-1 were prepared as potential nitric oxide donors. The synthesis of SCP analogs was achieved by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by …

Flavonoid And Cannabidiol Neural Glyoxalase Pathway Enhancement Against Aging And Alzheimer’S Disease, Joel R. Frandsen

Theses & Dissertations

Alzheimer’s Disease is a neurodegenerative condition featuring neural cell death and a decline in cognitive capacity caused by elevated inflammation and production of reactive oxygen species. The glyoxalase pathway is an endogenous antioxidant system that neutralizes reactive methylglyoxal through sequential reactions. Dysfunction of the glyoxalase pathway contributes to oxidative stress and the accumulation of inflammatory metabolic byproducts. Plant-produced compounds with antioxidant activity can enhance endogenous antioxidant pathways and protect cells from elevated ROS production. We hypothesize that flavonoids and limited Cannabis Sativa-produced cannabidiol can enhance glyoxalase pathway function through regulation of antioxidant and pro-apoptotic signaling pathways to prevent methylglyoxal-mediated …

Isolation, Identification, And Investigation Of A Novel Bioactive Furanocoumarin From Leaves Of Amyris Elemifera, Amy K. Bracken

Honors Theses

Plants produce biologically active compounds that humans have utilized for many agricultural applications. Amyris elemifera was investigated due to the known bioactivity of its family, Rutaceae, and its use in medicines in tribes of the Bahamas. Biotage® and TLC guided fractionation of the EtOAc, hexane, and MeOH extracts of the leaves of Amyris elemifera yielded bioactive compounds. Most significantly, a novel furanocoumarin, 8-(3-methylbut-2-enyloxy)-marmesin acetate (1), and its analog 8-(3-methylbut-2-enyloxy)-marmesin (2), were isolated. The structures were identified via NMR and X-ray crystallography techniques; the X-ray crystal structure for 1 was reported for the first time, and the …

Approaches Towards The Synthesis Of Ketamine Metabolites, Ann K. Patrick

Honors Theses

Major Depressive disorder (MDD) plagues society and stands at the forefront of research as MDD affects approximately 16% of the population. Pharmaceutical drugs, including the selective serotonin reuptake inhibitors (SSRIs), have been used for MDD treatment and remain a popular option today. However, current antidepressant treatments have proven to be ineffective in just less than half of the patients. Research continues with the goal to better understand the mechanisms of the pathology of depression and to search for other treatment options. For example, the stress-neurogenesis hypothesis investigates the role of stress and decreased neuroplasticity within MDD.

Supporting the stress-neurogenesis hypothesis, …

Silver-Catalyzed Synthesis Of Disubstituted Fluorinated Isoxazoles, Micah Stewart

Honors Theses

The presence of fluorine can provide organic compounds with useful biological properties, such as increased metabolic stability and drug uptake. Because of these advantages, fluorinated compounds make up about 30% of the drug industry. However, fluorination of complex molecules is difficult due to fluorine’s high electronegativity.

Fluorinated isoxazoles are of particular interest in the pharmaceutical industry. Isoxazoles are five-membered heterocycles with oxygen and nitrogen in the 1, 2 positions that are able to engage in interactions unavailable to other ring structures, conferring advantageous biological properties upon compounds containing them. However, there are limited synthetic routes for fluorinated isoxazoles, and those …

Structure Activity Relationship (Sar) Studies Of Neurotoxin Quinoline-Derivatives, Dylan Smeyne

Honors College Theses

Structure activity relationship (SAR) studies are performed in order to identify the core structure that is responsible for the biological activity of an organic molecule. Recently, we have synthesized a drug prototype which contains several functional groups, such as an alcohol, an ester, a fluorine, and an aromatic ring. While studying in vivo toxicity of this molecule in zebrafish (Danio rerio) embryo, we observed that it has a unique biological activity that causes a sudden inactivity in embryo movement. Continued investigation revealed that this molecule blocks sodium channels in neurons causing a temporary anesthesia in Danio rerio embryo. The biological …

Synthesized Tripodal Amine As Potential Anti-Cancer Therapeutic, Abigail G. Mcnamee

Honors College Theses

Cancer remains a prevalent disease today. This disease may manifest itself in many different ways and affect a variety of tissues with everything from the brain to the blood. With this wide diversity of cancer types, treatment can be complicated since there is not a “one size fits all” treatment for the disease. Surgery, radiation, and chemotherapy are all options that must be weighed with their benefits and side effects. Ultimately though, there are not enough effective treatment options available for every type of cancer. This leaves many with the grim prognosis of never being cured. With this clear need …

Computational Chemistry - Ulk 101, Michaela Montpas

Scholar Week 2016 - present

Autophagy is a process that generates the necessary building components for cells by cytoplasmic breakdown of unnecessary materials (Martin, Celano, Solitro, Gunaydin, Scott, et. al., 2018). This is a survival technique for cells in times of stress, especially during periods of nutrient starvation. Cancer cells, unfortunately, benefit from this process due to their ability to flourish in nutrient-starved environments, becoming resistant to therapy. The primary protein in mammals responsible for this process is a serine/threonine kinase called ULK 1 (unc-51 like autophagy initiating kinase 1). As such, inhibitors of ULK 1 can be used in cancer therapies in order to …

Research And Review Of Polymethyl-Methacrylate Copolymers In The Development Of Enhanced Pharmaceutical Delivery Systems, Jake Dyess

Senior Honors Theses

The following thesis shall primarily explore the current research regarding the implementation of modifiable microscopic and nanoscopic polymer particles as novel pharmaceutical delivery systems. Polymethacrylate-based copolymers, such as Eudragit^TM, are sensitive to alterations in pH levels, becoming increasingly more soluble in response to an increase in pH. The selective solubility and modifiable nature of these polymers allows for greater flexibility of treatment options for patients (Patra et al., 2017). The wide range of functionality of polymethacrylate (PMA) may provide solutions to challenges relating to the current treatment and therapy of certain conditions. Research indicates that PMA based micro- …

To Probe Full And Partial Activation Of Human Peroxisome Proliferator-Activated Receptors By Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations., Holli-Joi Sullivan, Xiaoyan Wang, Shaina Nogle, Siyan Liao, Chun Wu

Faculty Scholarship for the College of Science & Mathematics

Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation …

Assessing The Correlation Of Microscopy-Based And Volumetry-Based Measurements For Resin Swelling In A Range Of Potential Greener Solvents For Spps, Jordan K. Magtaan, Marc Devocelle, Fintan Kelleher

Articles

The degree of resin swelling in a particular solvent system is one of the critical parameters for SPPS, and for solid phase synthesis, in general. Methods used for measuring the degree of resin swelling include microscopy-based and volumetry-based methods. This study describes, and compares, the use of both methods for a number of commercially available resins commonly used in SPPS, with a range of solvents which have been identified in the literature as “greener” than DCM, DMF and NMP. The results were analysed by statistical methods and a significant correlation between the two distinct methods has been demonstrated for the …

Analysis Of Hydroxychloroquine Interaction With Serum Proteins By High Performance Affinity Chromatography, Kyungah Suh, Sadia Sharmeen, David S. Hage

Department of Chemistry: Dissertations, Theses, and Student Research

Personalized medicine or precision medicine has been an emerging market for better treatments of patients under varying physiological conditions.To improve the development of personalized medicine, a higher understanding of drug-protein binding between serum transport proteins and the unbound form of pharmaceuticals is needed. Human Serum Albumin (HSA) and Alpha1-acidglycoprotein (AGP) play a crucial role in pharmacokinetics as they are two most abundant transport serum proteins in body circulatory system. Inter-individual variabilities of serum proteins, such as the physiological condition of patients, have been believed to alter the drug-serum protein binding. Fig. 1 shows an example of the cause of inter-individual …

Force Field Development Of Β-Lactam Class Antibiotics, Trevor Heinzmann

SMU Journal of Undergraduate Research

Molecular dynamics (MD) simulation is a computational chemistry technique used to observe how a molecular system behaves as time passes. MD is based on solving Newton’s equations of motion. This requires the use of force fields to describe the potential energy function of each different molecule type in molecular system. In order to develop a force field, charges, bonds, angles, and dihedrals must be parameterized to fit quantum mechanics (QM) data. By basing the force field on QM data, MD simulations have higher accuracy while still using the low computational cost of molecular mechanics. This project focuses on developing well-fit …

Resolving The Puzzle Of Single-Atom Silver Dispersion On Nanosized Γ-Al2o3 Surface For High Catalytic Performance, Fei Wang, Jinzhu Ma, Shaohui Xin, Qiang Wang, Jun Xu, Changbin Zhang, Hong He, Xiao Cheng Zeng

Chemistry Department: Faculty Publications

Ag/γ-Al2O3 is widely used for catalyzing various reactions, and its performance depends on the valence state, morphology and dispersion of Ag species. However, detailed anchoring mechanism of Ag species on γ-Al2O3 remains largely unknown. Herein, we reveal that the terminal hydroxyls on γ-Al2O3 are responsible for anchoring Ag species. The abundant terminal hydroxyls existed on nanosized γ-Al2O3 can lead to single-atom silver dispersion, thereby resulting in markedly enhanced performance than the Ag cluster on microsized γ-Al2O3. Density-functional-theory calculations confirm that Ag atom is mainly anchored by the terminal hydroxyls on (100) surface, forming a staple-like local structure with each Ag …