Medicinal-Pharmaceutical Chemistry Commons^™

The Development Of Novel Radioimmunoconjugates For The Pet Imaging And Radioimmunotherapy Of Cancer, Samantha M. Sarrett

Dissertations, Theses, and Capstone Projects

Antibodies have long played a vital role in nuclear medicine for both the diagnosis and therapy of various malignancies. The role and development of antibodies in nuclear medicine can be broadly separated into three different categories: 1) bioconjugation strategies, 2) immunoPET imaging, and 3) radioimmunotherapy. This dissertation will attempt to comprehensively cover each of these categories through a series of studies, protocols, and reviews. For the bioconjugation strategies, we will describe the development of a novel site-selective bioconjugation strategy using an innovative lysine-targeting reagent, PFP-bisN₃, to prepare [⁸⁹Zr]Zr-^SSKDFO-pertuzumab for visualizing HER2+ breast cancer. Further, …

Synthesis And Analysis Of Novel Troponoid-Based Chemical Probes, Alex Berkowitz

Dissertations, Theses, and Capstone Projects

Troponoids are a class of non-benzenoid aromatic species featuring a cycloheptatrienone ring and varying degrees of oxygenation. These scaffolds have proven ubiquitous amongst natural products, and have displayed promise as therapeutic agents against a variety of diseases. Herein, we will describe our efforts towards furthering troponoids as potential pharmaceuticals. In Chapter 1, we outline a kojic acid-derived oxidopyrylium cycloaddition/ring-opening method developed in our lab to generate ahydroxytropolones (aHTs). This route was successfully adapted to synthesize a small library of lipophilic aHTs that were proven to be effective against herpes simplex virus-1 (HSV-1) replication, while providing further insight into the mechanism …

Water-Based Lead Generation, Brian Olson

Dissertations, Theses, and Capstone Projects

Water-based Lead Generation. The opioid epidemic and the SARS-CoV-2 pandemic are current serious challenges whose devastating effects could be assuaged through the development of new drugs. Opioids that are functional painkillers, that are less likely to cause overdose, and small molecule drugs that could inhibit the life cycle of SARS-CoV-2 would be useful. The work herein investigated the use of water molecules for lead generation in drug development against opioid receptors and SARS-CoV-2 viral proteins. In opioid receptor binding sites, purported bridging waters were obtained from crystal waters or from molecular dynamics simulations, as Hydration Site Analysis was used to …

Probing The Production Of Intracellular Vesicles Containing Reactive Oxygen And Nitrogen Species By Electrochemical Resistive-Pulse Sensing, Rui Jia

Publications and Research

No abstract provided.

Biomedical Applications Of Lanthanide Nanomaterials, For Imaging, Sensing And Therapy, Qize Zhang, Stephen O'Brien, Jan Grimm

Publications and Research

The application of nanomaterials made of rare earth elements within biomedical sciences continues to make significant progress. The rare earth elements, also called the lanthanides, play an essential role in modern life through materials and electronics. As we learn more about their utility, function, and underlying physics, we can contemplate extending their applications to biomedicine. This particularly applies to diagnosis and radiation therapy due to their relatively unique features, such as an ultra-wide Stokes shift in the luminescence, variable magnetism and potentially tunable properties, due to the library of lanthanides available and their multivalent oxidation state chemistry. The ability to …

The Temperature-Dependent Conformational Ensemble Of Sars-Cov-2 Main Protease (Mpro), Ali Ebrahim, Blake T. Riley, Desigan Kumaran, Babak Andi, Martin R. Fuchs, Sean Mcsweeney, Daniel A. Keedy

Publications and Research

The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M^pro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M^pro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M^pro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M^pro, including …

Enhanced Platinum (Ii) Drug Delivery For Anti-Cancer Therapy, Marek T. Wlodarczyk

Dissertations, Theses, and Capstone Projects

Over the years, anti-cancer therapies have improved the overall survival rate of patients. Nevertheless, the traditional free drug therapies still suffer from side effects and systemic toxicity, resulting in low drug dosages in the clinic. This often leads to suboptimal drug concentrations reaching cancer cells, contributing to treatment failure and drug resistance. Among available anti-cancer therapies, metallodrugs are of great interest. Platinum (II)-based agents are highly potent and are used to treat many cancers, including ovarian cancer (OC). Cisplatin (cis-diaminedichloroplatinum (II)) is the first Food and Drug Administration (FDA)-approved metallodrug for treatment of solid tumors, and its mechanism …

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 …

Triflic Acid Mediated Sequential Cyclization Of Ortho-Alkynylarylesters With Ammonium Acetate, Maciej E. Domaradzki, Xiaochen Liu, Jiye Ong, Gyeongah Yu, Gan Zhang, Ariel Simantov, Eliyahu Perl, Yu Chen

Publications and Research

A triflic acid (TfOH) mediated sequential cyclization of ortho-alkynylarylesters and ammonium acetate (NH₄OAc) was reported. The reaction took place via a Brønsted acid-mediated intramolecular cyclization of ortho-alkynylarylesters followed by an ammonium acetate participated substitution reaction, forming isoquinolin-1-ones as the major products. Different from most of the known synthetic methods of isoquinolin-1-ones, no metal catalyst was required in the reported reaction. The regioisomers – isoindolin-1-ones were obtained together with isoquinolin-1-ones in a few cases. The intermediate compounds – isochromen-1-ones and isobenzofuran-1-ones were also isolated. The interconversion experiments showed that the regioisomers formed during the Brønsted acid induced …

Development Of A Screening Method For Drugs Of Abuse By Direct Analysis Of Dried Urine Spots Coupled To Mass Spectrometry, Melanie Goldstein

Student Theses

Fast and easy screening procedures are essential in any forensic toxicology laboratory to differentiate negative samples from presumptive positive cases. Immunoassay techniques, such as enzyme multiplied immunoassay technique (EMIT), are routinely employed as screening procedures. However, these techniques lack specificity (only differentiate group of drugs and not individual compounds) and it is difficult to add new compounds to the panel. Direct analysis of dried urine spots (DUS) by mass spectrometry (MS) offers a novel strategy to overcome these issues. DUS offer an improved storage alternative for biological samples, reducing costs and space requirements. In this work, an original method to …

Determination Of Anxiolytic And Antidepressant Medicines In New York City Wastewater Samples, Jasmine J. Gayle

Student Theses

Wastewater-based epidemiology (WBE) provides information about a population’s exposure to certain chemical agents, such as drugs of abuse and medicines, by the analysis of human biomarkers, also known as excretion products, in wastewater samples. Although this is a growing field worldwide, mainly in Europe, Oceania, and Asia, limited data from the US are currently available. We developed and validated an analytical method to quantitatively and qualitatively determine the presence of commonly prescribed drugs to treat anxiety (alprazolam, buspirone, clonazepam, lorazepam, and propranolol) and depression (bupropion, citalopram, clomipramine, duloxetine, fluoxetine, imipramine, paroxetine, sertraline, and venlafaxine) in wastewater using liquid chromatography tandem …

Preparation Of Enantioenriched Alkyltin Species And Their Application In Stereospecific Transformations, Glenn O. Ralph

Dissertations, Theses, and Capstone Projects

Organometallic reagents containing the tin-carbon bond are used extensively in modern synthetic chemistry for the formation of new bonds to carbon. Over recent decades, transition metal catalyzed cross coupling reactions between two C(sp²) centers have been widely developed. However, the introduction of a C(sp³) center complicates the catalytic cycle, and opens unproductive chemical pathways which lead to isomerization, elimination, and racemization. Our lab has developed a modified-Stille reaction to combat the deleterious effects of β-hydride elimination. Our protocol enables unactivated 2° alkyl organotin nucleophiles to undergo efficient cross coupling reactions with C(sp²) electrophiles, avoiding …

A Pretargeted Spect Imaging Strategy Employing Technetium-99m Based On Bioorthogonal Diels-Alder Click Chemistry, Justin H. Walsh

Dissertations, Theses, and Capstone Projects

A series of related N₃S ^99mTc-peptide complexes were synthesized and tested for use in pretargeting SPECT imaging that utilizes the bioorthogonal Diels-Alder click reaction between tetrazine (Tz) and transcyclooctene (TCO). The objective was to optimize the excretory pathways of the ^99mTc-peptide complexes for maximum tumor targeting with the in vivo “click” and minimum non-target uptake. The ^99mTc–tetrazine constructs were prepared by reaction of ^99mTc-peptide complexes (^99mTc-FKC, ^99mTc-FKCR, ^99mTc-DKC, and ^99mTc-SKC) with Tz-NHS or Tz-PEG₅-NHS to form ^99mTc FK(Tz)C, ^99mTc-FK(PEG₅-Tz)CR, ^99mTc-DK(PEG₅-Tz)C, …

Bisthioether Stapled Peptides Targeting Polycomb Repressive Complex 2 Gene Repression, Gan Zhang

Dissertations, Theses, and Capstone Projects

Interactions between proteins play a key role in nearly all cellular process, and therefore, disruption of such interactions may lead to many different types of cellular dysfunctions. Hence, pathologic protein-protein interactions (PPIs) constitute highly attractive drug targets and hold great potential for developing novel therapeutic agents for the treatment of incurable human diseases. Unfortunately, the identification of PPI inhibitors is an extremely challenging task, since traditionally used small molecule ligands are mostly unable to cover and anchor on the extensive flat surfaces that define those binary protein complexes. In contrast, large biomolecules such as proteins or peptides are ideal fits …

Synthesis And Evaluation Of Troponoids As A New Class Of Antibiotics, Feng Cao, Cari Orth, Maureen J. Donlin, Patrick Adegboyega, Marvin J. Meyers, Ryan P. Murelli, Mohamed Elagawany, Bahaa Elgendy, John E. Tavis

Publications and Research

Novel antibiotics are urgently needed. The troponoids [tropones, tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial activity. We synthesized or purchased 92 troponoids and evaluated their antibacterial activities against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Preliminary hits were assessed for minimum inhibitory concentrations (MIC80) and cytotoxicity (CC50) against human hepatoma cells. Sixteen troponoids inhibited S. aureus/E. coli/ A. baumannii growth by ≥80% growth at <30 >μM with CC50 values >50 μM. Two selected tropolones (63 and 285) inhibited 18 methicillin-resistant S. aureus (MRSA) strains with similar MIC80 values as against a reference strain. Two selected thiotropolones (284 and 363) …

Greer Studies, Teaches How To Improve Medicines, Aldemaro Romero Jr.

Publications and Research

“As a child, I was interested in asking questions. Like why different substances work the way they do and why they have some effect on our bodies. I was fascinated by hydrogen-peroxide and how it decomposes when you pour it on the wound. I would ask why it happens, what is the reason?” That’s how Dr. Edyta Greer explains how she became interested in science. A native of Poland, Greer received her master’s from Warsaw University and her doctorate from the Graduate Center of the City University of New York. Today she is an associate professor in the Department of …

Discovery And Development Of A Three-Component Oxidopyrylium Cycloaddition And Its Application Towards Alpha-Hydroxytropolone Synthesis, Michael P. D'Erasmo

Dissertations, Theses, and Capstone Projects

Historically, natural products have provided unique research opportunities and challenges for organic synthesis, chemical biology, and medicinal chemistry due to their molecular complexity and effects on physiological systems. The total synthesis of natural products has not only produced novel reaction methods and strategies capable of efficiently generating complex structural motifs but also granted access to sufficient quantities of otherwise scarce natural product material for clinical evaluation. These synthetic efforts have facilitated the formation of a transdisciplinary partnership between chemistry, biology, and medicine that has been paramount in elucidating the chemical and pharmaceutical utility of natural products. Chapter I of this …

The Therapeutic Potential Of Natural Products From Vaccinium Berries For Viral And Lung Diseases Through An Improved Lc-Ms-Based Chemometric Approach, Vanya I. Petrova

Dissertations, Theses, and Capstone Projects

Smoking is a global epidemic that creates serious health and economic burden. It is the primary, preventative factor for the majority of causes of death worldwide. Analysis of publicly available data revealed that smoking prevalence rates among the youth in developing countries, especially in Bulgaria, are alarmingly high. The Bulgarian population has one of the highest percentages of smokers and the second highest rate among teenage girls. Consequently, chronic diseases affected by smoking, such as chronic obstructive pulmonary disorder (COPD), have been increasing there in the last five years. Poland, on the other hand, is an exemplary outlier for the …

From The Making To The Tuning To The Use Of Chlorins For Biomedical Applications, Junior Gonzales

Dissertations, Theses, and Capstone Projects

Chlorins are porphyrins missing a double bond. These pigments are optimal platforms for the development of novel dyes that display drug-like attributes such as photodynamic therapy (PDT) agents. More recently, it was demonstrated that chlorins can serve both as a PDT agent and as a modality for fluorescence or PET imaging. Thus, multifunctional chlorins eliminate the differences that may occur in specificity, uptake, and distribution between separate compounds or constructs for imaging and therapy. The overall goal of this dissertation is to take advantage of the reputed intrinsic attributes of chlorins as a viable tool in biomedical applications. In this …

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 …

Ionophoric Polyphenols Selectively Bind Cu2+, Display Potent Antioxidant And Anti-Amyloidogenic Properties, And Are Non-Toxic Toward Tetrahymena Thermophila, Alberto Martinez, Ralph Alcendor, Tanzeen Rahman, Magdalena Podgorny, Ismaila Sanogo, Rebecca Mccurdy

Publications and Research

Alzheimer’s disease (AD) is the most common form of dementia affecting more than 28 million people in the world. Only symptomatic treatments are currently available. Anticipated tri-fold increase of AD incidence in the next 50 years has established the need to explore new possible treatments. Accumulation of extracellular amyloid-b (Ab) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. The active role of some metal ions, especially Cu²⁺, in promoting both Ab aggregation and reactive oxygen species formation has rendered ionophoric drugs as a promising treatment strategy. …

The Synthesis Of Angucyclines Using An Intramolecular Bradsher Cycloaddition, Abdullah Allaoa, Tony E. Nicolas

Publications and Research

The Angucyclines are natural products which possess a broad spectrum of biological properties. Of particular interest are the natural products which contain the cis-hydroxyl motif at the AB ring junction. Their synthesis is particularly challenging. Our model study has resulted in the synthesis of a model of the angucyclines with the required cis-hydroxyl features. The present work will apply the previously developed chemistry to an intramolecular version which will lead to the synthesis of the ABC ring system

Synthesis Of Novel Aporphine-Inspired Neuroreceptor Ligands, Nirav R. Kapadia

Dissertations, Theses, and Capstone Projects

Aporphines are a group of tetracyclic alkaloids that belong to the ubiquitous tetrahydroisoquinoline family. The aporphine template is known to be associated with a range of biological activities. Aporphines have been explored as antioxidants, anti-tuberculosis, antimicrobial and anticancer agents. Within the Central Nervous Systems (CNS), aporphine alkaloids are known to possess high affinity for several clinically valuable targets including dopamine receptors (predominantly D₁ and D₂), serotonin receptors (5-HT_1A and 5-HT₇) and α adrenergic receptors. Aporphines are also inhibitors of the acetylcholinesterase enzyme – a clinical target for the treatment of Alzheimer’s disease. Considering the …

Polycations Xxii. Ru(Bpy)2l2 And Ru(Phen)2l2 Systems With Cationic 4,4’-Bipyridine Ligands: Syntheses, Characteristics, And Interactions With Dna, Jasmine Hatcher, Freida Zavurov, Leslie Babukutty, Thomas Strekas, Robert Engel

Publications and Research

Earlier efforts have been concerned with the association of Ruthenium octahedral complexes with DNA. Since the positively charged ruthenium species has been found to associate with the electron rich major groove of double-stranded DNA, it was proposed the addition of cationic sites on the ligands attached to ruthenium would facilitate such association. Thus, we have synthesized several series of octahedral ruthenium complexes bearing ligands having within themselves cationic sites. These have been investigated in their interaction with calf thymus DNA using fluorescence titration analysis. The introduction of the cationic ligands has been found to exhibit enhanced association of the ruthenium …

Supercharging: An Investigation Into The Effects Of External Amino Acid Residue Charge On The Solubility And Internal Electric Character Of Bound Ligands In A Heme-Binding De Novo-Designed Protein, Cooper French

Dissertations and Theses

De novo protein design offers many interesting prospects both as a means to better understand natural protein dynamics and as a potential resource in biomedical and industrial applications. In this work I describe the modification of a simple, well-characterized heme-binding protein by altering side chain residue identities on the hydrophilic surface of the protein to produce variants with a range of net external charges. These charge modifications had a significant impact on nearly every measurable character of the protein. This work establishes the hard limits of supercharging within our experimental protein scaffold system, demonstrating that excessive positive charge increased the …