Medicinal-Pharmaceutical Chemistry Commons^™

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 …

Purification And Isolation Of Α-Chloro-Β-Lactone Precursor Molecules, Matthew Ellis

ASPIRE 2024

This research investigates the synthesis of α-chloro-β-lactone molecules, focusing on the production, isolation, and purification of two precursor compounds from chloroacetic acid and substituted benzaldehydes. While multiple methods were explored, including EDC, DIC, and DCC catalysis, DCC proved to be most effective in producing higher yields. However, challenges in purification arose due to the formation of byproducts, particularly with DCC, prompting further investigation for efficient extraction and purification techniques. DCC, however, shows a promising route for α-chloro-β-lactone synthesis, despite purification complexities.

Frontiers In The Self-Assembly Of Charged Macromolecules, Khatcher O. Margossian

Doctoral Dissertations

The self-assembly of charged macromolecules forms the basis of all life on earth. From the synthesis and replication of nucleic acids, to the association of DNA to chromatin, to the targeting of RNA to various cellular compartments, to the astonishingly consistent folding of proteins, all life depends on the physics of the organization and dynamics of charged polymers. In this dissertation, I address several of the newest challenges in the assembly of these types of materials. First, I describe the exciting new physics of the complexation between polyzwitterions and polyelectrolytes. These materials open new questions and possibilities within the context …

Identification And Quantitation Of Unspecified Impurities Discovered In Novel Oral Irinotecan By Lc-Ms/Ms And Uhplc, Laura B. Miller

Forensic Science Master's Projects

Irinotecan is a cancer medication approved for medical use in the United States in 1996. It is currently administered via intravenous injection. However, intravenous dosing has disadvantages such as requirement of administration by a trained professional in a medical facility, possible severe adverse effects, pain at the injection site, and possible hemolysis if injected too rapidly. Previously oral administration was not feasible because the p-glycoprotein (p-GP) on the cell membrane of stomach cells acts as a defense mechanism against harmful substances by pumping the irinotecan back into the intestinal lumen for excretion. With the discovery of the p-GP inhibitor encequidar …

Synthesis, Characterization, And Bioactivity Of 3-Substituted Coumarins As An Undergraduate Project, Karsen King, Nicholas Campbell, Ronald Okoth, Wathsala Medawala

Georgia Journal of Science

Coumarins are an important class of phytochemicals, a chemical defense presumed to be secreted by plants. More recently, Coumarins have gathered popularity for their basis in anti-cancer agents. This paper dives into the organic synthesis of two 3-substituted coumarins from o-vanillin using the Knoevenagel condensation reaction. The 3-substituted coumarin were characterized using melting point analysis, ¹H-NMR, and UV-Vis spectroscopy. In addition, the anticancer activity of synthesized 3-substituted coumarin compounds were assayed against topoisomeraseIIα, which is the target enzyme of FDA approved anti-cancer drug etoposide since it is an active enzyme in cancer cell replication. The demonstrated procedures can be …

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 …

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 …

Characterization Of Lamellar Liquid Crystal Emulsifiers In Topical Creams Containing A Novel Solvent, Melinda Joanna Sutton

MSU Graduate Theses

Diethylene glycol monoethyl ether (DEGEE) is a promising solvent component in topical cream formulations due to its superior solubilizing abilities with certain active pharmaceutical ingredients. One of the goals of this study is to characterize the effects of pH on the physical and chemical stabilities of topical cream formulations containing particularly high concentrations of DEGEE by characterizing a full topical pH profile of 3.5 – 9.0. The second goal is to evaluate the presence, amount, and characteristics of lyotropic liquid crystals (LLCs), molecularly structured in a lamellar phase, in a model cream emulsion utilizing polarized light microscopy (PLM). The presence …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Philippine Medicinal Plants With Potential Immunomodulatory And Anti-Sars-Cov-2 Activities, Fabian M. Dayrit, Armando M. Guidote Jr, Nina Gloriani, Sheriah Laine M. De Paz-Silava, Irene M. Villaseñor, Rene Angelo S. Macahig, Mario A. Tan, John Ross N. Chua, Isidro C. Sia

Chemistry Faculty Publications

Coronavirus disease 2019 (COVID-19) continues to devastate the world’s health and economy, affecting all aspects of life leading to widespread social disruption. Even as several vaccines have been developed, their availability in developing countries is limited and their efficacy against the variants of SARS-CoV-2 (severe acute respiratory syndrome–coronavirus 2) needs to be continuously assessed. The World Health Organization (WHO) has acknowledged that vaccines alone will not overcome the global challenges of COVID-19. Medicinal plants may provide the needed support. Herein, we identify Philippine medicinal plants that possess phytochemicals with potential anti-SARS-CoV-2 activity and/or immunomodulatory properties that may strengthen one’s immune …

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 …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Mechanistic Studies And Derivative Effects In 1, 3, 4- Oxadiazole Synthesis Via Cyclodehydration Reactions, Evan Huggins

Undergraduate Honors Thesis Projects

In the world of pharmaceutical synthesis, research to combat foreign pathogens is always necessary. Scientists have been exploring different methods in order to synthesize the most effective compounds in antibacterial, anticancer, anti-inflammatory, and many other treatments. A key component within these versatile compounds are 1,3,4-oxadiazoles. Current methods to synthesize these compounds are inefficient. This research seeks to improve oxadiazole synthesis; however, the mechanism of this reaction is unknown. The goal of this project was to study the mechanistic pathway in the discovered, one-pot cyclodehydration synthesis of 1,3,4-oxadiazoles. In the first part of this study, a diacylhydrazine intermediate was proposed. This …

Synthesis Of A Sulfur Variant For Treatment Of Trypanosomiasis, Carlos Vera-Esquivel

UNO Student Research and Creative Activity Fair

Previous work in our lab has found diphenyl ether benzylamines showed a successful response with a micromolar concentration of our lead compound to treat the deadly Trypanosamiosis rhodesience. Furthermore, mammalian cell lines saw promising resistance towards damages. The goal of this study was to synthesize a diphenyl thio benzylamine variant. This variant was more active toward T. b. rhodesience but showed more toxicity to both rat 10 (IC₅₀ mM) and human cell lines (HFF, HC-₀₄, U-₂ OS, and HEK₂₉₃). The selectivity index (ratio of toxicity to activity in the same concentration units (SI)) …

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.

Preparation Of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles For Pharmaceutical Applications, Kate E. Frischkorn

Master's Theses

Recent pharmaceutical developments have investigated using supramolecular nanoparticles in order to increase the bioavailability and solubility of drugs delivered in various methods. Modification of the carbohydrate cyclodextrin increases the ability to encapsulate hydrophobic pharmaceutical molecules by forming a carrier with a hydrophobic core and hydrophilic exterior. Guest molecules are commonly added to these inclusion complexes in order to add stability and further increase targeting abilities of the carriers. One such guest molecule is adamantine combined with a poly(ethylene glycol) chain. Vesicles are formed by hydrating a thin film of amphiphilic cyclodextrin and guest molecules in buffer solution that mimics physiological …

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 …

Synthesis Of Multifunctional Polyacrylates And A Binding Group To Hemoglobin For The Treatment Of Traumatic Brain Injuries, Marina Michaud

Honors College Theses

Hemoglobin based oxygen carriers (HBOCs) hold promise as an effective emergency treatment of severe traumatic brain injuries (TBI). In the latest generation of HBOCs, polynitroxyl-pegylated hemoglobin (PNPH), cell-free hemoglobin is modified with TEMPO and PEG which reduce the toxicities associated with earlier generations of HBOCs. In our efforts to optimize the economic and therapeutic impacts of PNPH’s we have synthesized polydimethylaminoethyl methacrylate (poly-DMAEMA) under controlled living conditions via reverse addition-fragmentation chain transfer (RAFT) polymerization. The poly-DMAEMA was then successfully functionalized via quaternization of its NMe₂ groups using chloroacetate derivatives of the TEMPO and PEG. This process was quantitative and …

Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun

Pharmacy Faculty Articles and Research

Derivatives of dasatinib were synthesized via esterification with 25 carboxylic acids including amino acids and fatty acids by extending the inhibitor to interact with more diverse sites and to improve specificity. Dasatinib-L-arginine derivative (Das-R, 7) was the most potent of the inhibitors tested with IC50 values of 4.4 nM, <0.25 nM, and <0.45 nM against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src belonged to compound 18 (Das-C10) with an IC50 of 3.2 μM for Csk compared to 35 nM for Src. Furthermore, many compounds displayed increased selectivity toward Src, as compared with Abl. Compounds 15 (Das-E) and 13 (Das-C) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 = 2.06 μM) was significantly more potent than Das (IC50 = 26.3 μM) against Panc-1 cells while they both showed an IC50 < 51.2 pM against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed a good agreement with the experimental results and rationalized differences in selectivity of the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of dasatinib scaffold, providing useful insights into mechanisms of kinase selectivity.

Distributed Drug Discovery: Synthesis Of Unnatural Amino Acids As Potential Antimalarial Drugs, Amanda Dugan

Honors College

Through the collaboration of many institutions across the globe, the Distributed Drug Discovery project founded at Indiana University-Purdue University Indianapolis seeks to aid in the development of drugs for the developing world. In response to two antimalarial assay hits, our team at Abilene Christian University has synthesized many unnatural amino acid analogs using resin-based combinatorial chemistry. Proton nuclear magnetic resonance spectroscopy has been used to characterize the compounds and thin layer chromatography to determine purity. All compounds were purified on hypersep cyanosilica columns.

Total Synthesis Of Biologically Active Natural And Unnatural Products, Julia Heimberger

Electronic Theses and Dissertations

Herbarin A and B were isolated from the fungal strains of Cladosporium herbarum found in marine sponges Aplysina aerophoba and Callyspongia aerizusa. Total synthesis of Herbarin A and B was achieved by carrying out a multi-step synthesis approach, and the antioxidant properties were evaluated using FRAP assay. Toxicity of these compounds was determined using a zebrafish embryo model. Furthermore, synthesis of C-6 alkyl-azaarene derivatives of nucleosides by Csp3-H bond functionalization were investigated. Effective incorporation of 2-methylazaarene moiety at the C-6 position of the protected inosine nucleoside provided a new class of compounds with anticipated enhanced biological activity.

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

Design, Synthesis And Biological Evaluation Of Novel Compounds With Cns-Activity Targeting Cannabinoid And Biogenic Amine Receptors, Alexander M. Sherwood

University of New Orleans Theses and Dissertations

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function.

The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at …

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

Chancellor’s Honors Program Projects

No abstract provided.

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …

Turning Stealth Liposomes Into Cationic Liposomes For Anticancer Drug Delivery, Vijay Gyanani

University of the Pacific Theses and Dissertations

Targeting the anticancer agents selectively to cancer cells is desirable to improve the efficacy and to reduce the side effects of anticancer therapy. Previously reported passive tumor targeting by PEGylated liposomes (stealth liposomes) have resulted in their higher tumor accumulation. However their interaction with cancer cells has been minimal due to the steric hindrance of the PEG coating. This dissertation reports two approaches to enhance the interaction of stealth liposomes with cancer cells. First, we designed a lipid-hydrazone-PEG conjugate that removes the PEG coating at acidic pH as in the tumor interstitium. However, such a conjugate was highly unstable on …

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. …

Sds Non-Acrylamide Polymeric Gel-Filled Capillary Electrophoresis For Molecular Size Separation Of Protein, Devon Andres

Honors Theses

Sodium dodecyl sulfide (SDS) non-acrylamide gel-filled capillary columns are a new technology being used for analysis and separation of biotechnology-derived proteins. This research was to compare this new technology to the current methods of SDS polyacrylamide gel electrophoresis (SDS-PAGE) and high-performance size-exclusion chromatography (HPSEC). The molecular mass of four different recombinant proteins were determined by two commercialized SDS non-acrylamide gel-filled capillary columns, SDS-PAGE, and HPSEC. The data obtained showed that the SDS non-acrylamide gel-filled capillary columns were compatible with the SDS-PAGE technique for molecular mass determination. HPSEC was shown to be unreliable for molecular weight determination. SDS non-acrylamide gel-filled capillary …