Organic Chemistry Commons^™

Synthesis Of Agents For The Treatment And Analysis Of Tropical Diseases, Jeanine Yacoub

USF Tampa Graduate Theses and Dissertations

Toxoplasmosis is an opportunistic disease caused by the protozoan parasite Toxoplasma gondii. The parasite is usually staved off by a healthy immune system and remains dormant in the body. In immunocompromised patients, the parasite can become active and spread throughout the body causing symptoms such as encephalitis, cognitive disorders, seizures, and death. Combination drug therapy is the usual treatment for toxoplasmosis; however, patients suffer from problems of intolerance, allergic reactions, and cytotoxicity. In an effort to identify new drug targets for toxoplasmosis, a series of compounds have been synthesized that can be used as tools to probe the unique …

The Detection And Quantitative Analysis Of Endocannabinoids And Endogenous Fatty Acid Amides In Apis Mellifera And Tribolium Castaneum, Perry Robert Mitchell Jr.

USF Tampa Graduate Theses and Dissertations

Endocannabinoids, and the fatty acid amides from which they are a member, have garnered greater scientific interest in the last two decades due to the cannabimimetic properties of these endogenous molecules. The most well-known of these is Anandamide, which has thus far been discovered in several species of animal ranging from C. elegans, fruit flies, to bovine and humans. Because of the importance and increasing impact of these compounds a brief overview is first presented herein, with a major focus on the N-acyldopamines due to the direct impact they potentially pose to human physiology.

Secondly, the detection and …

Gamma-Aapeptides As A New Class Of Peptidomimetics: Synthesis, Structures, And Functions, Haifan Wu

USF Tampa Graduate Theses and Dissertations

Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant …

Design And Synthesis Of Bioactive Peptidomimetics, Yaogang Hu

USF Tampa Graduate Theses and Dissertations

Protein-Protein Interactions (PPIs) play a very important role in biological functions and therefore the inhibition of specific Protein-Protein Interactions has a huge therapeutic value. The most successful small molecular PPIs inhibitors do not fit with the prevalent `Rule of Five' drug profile. To overcome the disadvantages of small molecular PPIs inhibitors, peptide based PPIs inhibitors were developed. Herein we describe the development of a new class of peptidomimetics AA-peptides. The AApeptides were designed based on chiral PNA backbone. Substitution of nucleobases yields AApeptides that are resistant to proteolysis and capable of mimicking peptides. Two types of AApeptides were discussed in …

Co(Ii) Based Metalloradical Catalysis: Carbene And Nitrene Transfer Reactions, Joseph B. Gill

USF Tampa Graduate Theses and Dissertations

Radical chemistry has attracted a large amount of research interest over the last few decades and radical reactions have recently been recognized as powerful tools for organic synthesis. The synthetic applications of radicals have been demonstrated in many fields, including in the synthesis of complex natural products. Radical reactions have a number of inherent synthetic advantages over their ionic counterparts. For example, they typically proceed at fast reaction rates under mild and neutral conditions in a broad spectrum of solvents and show significantly greater functional group tolerance. Furthermore, radical processes have the capability of performing in a cascade fashion, allowing …

Chiral Phosphoric Acids And Alkaline Earth Metal Phosphates Chemistry, Tao Liang

USF Tampa Graduate Theses and Dissertations

Asymmetric synthesis and catalysis is one of the leading research areas in chemistry society, for its versatility and efficiency in obtaining chiral molecules that found the vast majority in natural active compounds and synthetic drugs. Developing asymmetric catalytic methodology is at the frontier in both industrial and academic research laboratories. Enantioselective organocatalysis has emerged as a powerful synthetic tool that is complementary to metal-catalyzed transformations. The development of chiral phosphoric acid and metal phosphate as catalysts has been a breakthrough in recent years. Chiral phosphoric acids have been shown to be powerful catalysts in many organic transformations. Moreover, chiral metal …

Synthesis Of [1,2,4]-Triazines As Kinase Inhibitors And Of Novel Fluorine Capture Reagents For Pet Probes, Fenger Zhou

USF Tampa Graduate Theses and Dissertations

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor, which plays a pivotal part in the development of the central nervous system. Aberrant expression of full-length ALK occurs in neuroblastoma and chromosomal translocation or inversion of the ALK gene can generate novel fusion-ALK proteins that possess constitutive kinase activity and contribute to oncogenic processes. One of the well-studied fusion proteins is nucleophosmin (NPM-ALK), which draws a lot of attention for medicinal chemists to design small molecules as kinase inhibitors for this target. In this dissertation, [1, 2, 4]-Dihydrotriazine dimers as competitors of the lead compound NVP-TAE684 targeting NPM-ALK have …

Synthesis And Evaluation Of 3-Aryl-4(1h)-Quinolones As Orally Active Antimalarials: Overcoming Challenges In Solubility, Metabolism, And Bioavailability, Andrii Monastyrskyi

USF Tampa Graduate Theses and Dissertations

Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly disease. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, …

Br[O/]Nsted Acid Catalyzed Asymmetric Allylation And Propargylation Of Aldehydes, Pankaj Jain

USF Tampa Graduate Theses and Dissertations

Carbonyl allylation and propargylation reactions have been an important tool for the stereocontrolled formation of carbon-carbon bonds for synthetic chemists. The chiral homoallylic and homopropargylic alcohols obtained from these reactions serve as versatile intermediates for the synthesis of natural and pharmaceutical products. Over the past three decades and continuing on, various synthetic groups around the globe have directed their research towards the efficient synthesis of these chiral moieties. In spite extensive research, asymmetric allylation and propargylation reactions remain an enduring challenge in organic chemistry.

Chapter 1 of this thesis describes the first phosphoric acid catalyzed asymmetric allylboration of aldehydes. We …

Diffusion Of Vitamin B12 Across A Mesoporous Metal Organic Framework, Veronica Valencia

Undergraduate Journal of Mathematical Modeling: One + Two

We measure the rate of uptake and the rate of release of a Vitamin B12 solution (dissolved in water) at 2 different temperatures (room temperature and 37°C) by the mesoporous metal organic framework TbMOF-100 at 1-hour intervals using a spectrophotometer. Using the Beer-Lambert law, we calculate the concentration of the stock solution based on the absorbance values obtained with the spectrophotometer. These values allow for the quantification of the initial rate of uptake and the rate of uptake at a random incubation time of the Vitamin B12 by the TbMOF-100. We also calculate the value of the coefficient of diffusion …

Synthesis Of Amphiphilic Α- And Γ-Aapeptides For Antimicrobial, Self-Assembly, And Mineralization Studies, Mohamad N. Amin

USF Tampa Graduate Theses and Dissertations

Seven novel, amphiphilic AApeptides were prepared. Two cationic, lipo-α-AApeptides, NA-75 and NA-77 were found to possess potent antimicrobial activity against Gram-positive bacteria, with almost no hemolytic activity. In addition to NA-75 and 77, four amphiphilic, γ-AApeptides, NA-133, 135, 137, and 139, and one anionic lipo-α-AApeptide, NA-81, were prepared for molecular self-assembly studies, with several interesting nanostructures observed by TEM. Mineralization of calcium carbonate from gaseous CO2 and Ca2+ in the presence of the 7 AApeptide amphiphiles was also observed by optical microscopy. Several AApeptides were found to be able to influence CaCO3 crystal morphology. Another α-AApeptide, NA-63, was synthesized by …

Chiral Phosphoric Acid-Catalyzed Acetalization And Iso-Pictet-Spengler Reactions, Matthew Jon Kaplan

USF Tampa Graduate Theses and Dissertations

The development of novel asymmetric reaction methodologies has been invaluable in both the academic and industrial world. In just 15 years, organocatalysis has provided a new means of developing asymmetric reaction methodologies using catalysts that are environmentally benign, relatively inexpensive, bench stable, and non-toxic. One development in organocatalysis that is important to our group in particular is chiral phosphoric acid-catalysis. BINOL-derived and VAPOL-derived phosphoric acids have proven to be excellent catalysts for a number of reactions.

The two projects I will discuss my efforts on are acetalization and iso-Pictet-Spengler reactions. These were projects that I performed during my first two …

Design, Synthesis And Evaluation Of Novel Diazirine Photolabels With Improved Ambient Light Stability And Fluorous-Based Enrichment Capacity, Arun Babu Kumar

USF Tampa Graduate Theses and Dissertations

Photoaffinity labeling is a quintessential technique in studying and analyzing the interaction between a ligand and receptor. Diazirines are one of the important photo-labile moieties used in photoaffinity labeling due to their superior photo labeling characteristics. Herein, we report the investigations we conducted with diazirine photolabels on (a) photochemical aspects leading to enhancement of their ambient light stability and (b) equipping them with fluorous tags to enable fluorous enrichment of labeled proteins. Furthermore, we report a pilot study to develop BACE-1 inhibitors, which have potential to be developed into photoaffinity probes.

3-Trifluoromethyl-3-phenyldiazirine offers good selectivity and protection against pseudolabeling but …

N-Acyl Ciprofloxacins: Synthesis, Antibacterial Activity And Effects On Molecular Loading Of Poly(Vinyl Benzoate) Nanoparticles, Ryan Cormier

USF Tampa Graduate Theses and Dissertations

Bacterial infections are becoming progressively more difficult to treat due to antibiotic resistance and the decreasing rate at which new antibiotics are brought to market. The Turos laboratory has attempted to tackle this problem for the last 15 years with the discovery of N-thiolated β-lactams leading to the design of polyacrylate nanoparticles to deliver these and other drugs. Chapter 1 discusses many reported instances of utilizing different types of polymeric nanoparticles to deliver antibiotics. Poly(lactic-co-glycolic acid) (PLGA), poly(alkyl cyanoacrylate) (PACA), poly(styrene-co-butylacrylate), and chitosan are the main polymers used to make nanoparticles. Chapter 2 describes the synthesis, antibacterial activity, and mechanism …

Design And Synthesis Of Protein-Protein Interaction Inhibitor Scaffolds, David B. Badger

USF Tampa Graduate Theses and Dissertations

Many currently relevant diseases such as cancer arise from altered biological pathways that rely on protein-protein interactions. The proteins involved in these interactions contain certain functional domains that are responsible for the protein's biological activities. These domains consist of secondary structural elements such as α-helices and Β-sheets which are at the heart of the protein's biological activity. Therefore, designing drugs that inhibit protein-protein interactions by binding to these key secondary structural elements should provide an effective treatment for many diseases. Presented in this dissertation are the designs, syntheses, and biological evaluations for both novel α-helix and novel Β-sheet mimics.

The …

Drug Discovery From Floridian Mangrove Endophytes, Jeremy Beau

USF Tampa Graduate Theses and Dissertations

A significant challenge of the 21st century is the growing health threat stemming from drug-resistant infectious diseases. There is an undeniable need to discover new, safe and effective drugs with novel mechanisms of action to combat this threat. A study of drugs currently on the market showed that natural products account for approximately 75% of new anti-infective drugs, either as new agents or analogs based upon their structure. Unfortunately, major pharmaceutical companies have cut back tremendously in natural products research in part due to the frustrating obstacle of frequent rediscovery of compounds. Fungi in particular are difficult to work with …

Synthesis And Anti-Mrsa Activity Of Hydrophilic C3-Acylated N-Thiolated Β-Lactams And N-Acyl Ciprofloxacin-N-Thiolated Β-Lactam Hybrids, Biplob Bhattacharya

USF Tampa Graduate Theses and Dissertations

The Turos laboratory has been working with N-thiolated β-lactams for years trying to understand the mode of action and structural features it needs to have biological activity. Over the years new data has shown promising inhibitory activity against various microbes.

In this dissertation, a review of the vast amount of work carried out on N-thiolated β-lactams in Turos laboratory has been done and their novelty, in terms of structure and mechanism has been discussed. A complete outline of our work in the discovery and ongoing development of these compounds, starting from our initial, unexpected finding of antimicrobial activity for one …

Chiral Binol Metal Phosphate/Phosphoric Acid Catalyzed Enantioselective Addition Of Phosphorus And Sulfur Nucleophiles To Imines And Epoxides, Gajendrasingh Ingle

USF Tampa Graduate Theses and Dissertations

The research presented in this dissertation focuses on chiral BINOL metal phosphatephosphoric acid catalyzed enantioselective additions of phosphorus and sulfur nucleophiles to imines and epoxides. In chapter 2, we reported a new method to synthesize chiral amino phosphine oxides. The reaction combines N-substituted imines and diphenylphosphine oxide catalyzed by chiral magnesium 9-antryl phosphate. A wide variety of aliphatic and aromatic aldimines substituted by electron neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The imines protected with dibenzocycloheptene protecting group provided better enantioselectivity than those protected with benzhydryl group, while both imines gave comparable yields. Also, …

Development And Optimization Of Kinetic Target-Guided Synthesis Approaches Targeting Protein-Protein Interactions Of The Bcl-2 Family, Sameer Shamrao Kulkarni

USF Tampa Graduate Theses and Dissertations

Kinetic target-guided synthesis (TGS) and in situ click chemistry are among unconventional discovery strategies having the potential to streamline the development of protein-protein interaction modulators (PPIMs). In kinetic TGS and in situ click chemistry, the target is directly involved in the assembly of its own potent, bidentate ligand from a pool of reactive fragments. Herein, we report the use and validation of kinetic TGS based on the sulfo-click reaction between thio acids and sulfonyl azides as a screening and synthesis platform for the identification of high-quality PPIMs. Starting from a randomly designed library consisting of nine thio acids and nine …

Enantioselective Brønsted And Lewis Acid-Catalyzed Reaction Methodology: Aziridines As Building Blocks For Catalytic Asymmetric Induction, Shawn E. Larson

USF Tampa Graduate Theses and Dissertations

Chiral molecules as with biological activity are plentiful in nature and the chemical literature; however they represent a smaller portion of the pharmaceutical drug market. As asymmetric methodologies grow more powerful, the tools are becoming available to synthesize chiral molecules in an enantioselective and efficient manner.

Recent breakthroughs in our understanding of phosphoric acid now allow for Lewis acid catalysis via pairing with alkaline earth metals. Using alkaline earth metals with chiral phosphates is an emerging approach to asymmetric methodology, but already has an influential record.

The development of new conditions for the phosphoric acid-catalyzed highly enantioselective ring-opening of meso-aziridines …

Development Of A Bio-Molecular Fluorescent Probe Used In Kinetic Target-Guided Synthesis For The Identification Of Inhibitors Of Enzymatic And Protein-Protein Interaction Targets, Katya Pavlova Nacheva

USF Tampa Graduate Theses and Dissertations

Abstract

Fluorescent molecules used as detection probes and sensors provide vital information about the chemical events in living cells. Despite the large variety of available fluorescent dyes, new improved fluorogenic systems are of continued interest. The Diaryl-substituted Maleimides (DMs) exhibit excellent photophysical properties but have remained unexplored in bioscience applications. Herein we present the identification and full spectroscopic characterization of 3,4-bis(2,4-difluorophenyl)-maleimide and its first reported use as a donor component in Forster resonance energy transfer (FRET) systems. The FRET technique is often used to visualize proteins and to investigate protein-protein interactions in vitro as well as in vivo. The analysis …

Asymmetric Intra- And Intermolecular Cyclopropanation By Co(Ii)- Based Metalloradical Catalysis, Xue Xu

USF Tampa Graduate Theses and Dissertations

Metal-catalyzed cyclopropanation of olefins with diazo reagents has attracted research interest because of its fundamental and practical importance. The resulting cyclopropyl units are recurrent motifs in biologically important molecules and can serve as versatile precursors in organic synthesis. Since they were first introduced in 2004, Co(II) complexes of D₂-symmetric chiral amidoporphyrins [Co(D₂-Por*)] have emerged as a new class of catalysts for asymmetric cyclopropanation. These metalloradical catalysts have been shown to be highly effective for asymmetric intermolecular cyclopropanation of a broad scope of substrates with different classes of carbene sources, particularly including electron-deficient olefins and acceptor/acceptor-substituted …

Synthesis Of Small Molecule Inhibitors Of Janus Kinase 2, Phosphodiesterase Iv, Gabaa And Nmda Receptors: Investigation Of Mcmurry, Mannich And Chemoenzymatic Strategies, Meghanath Gali

USF Tampa Graduate Theses and Dissertations

Stilbenoids possess a wide range of biological properties such as, anticancer, antiplatelet aggregation, antiestrogenic, antibacterial, antifungal and antiatherogenic, etc. Owing to these therapeutic values, a great deal of attention attracted in the synthesis of derivatives of stilbenes. During the course of the study, G6 a novel stilbenoid was discovered, through high throughput screening, to be a potent inhibitor of mutated JAK2-V617F. The mutated JAK2 variant has been implicated in various myeloproliferative disorders (MPDs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has been targeted by therapeutics. Chapter 2 describes the synthesis of analogs of the stilbenoid G6 …

Synthesis And Antimicrobial Activities Of S,S'-Heterosubstituted Disulfides, Praveen Ramaraju

USF Tampa Graduate Theses and Dissertations

Antibiotic resistance is a particularly critical health concern and has increased dramatically over the past two decades. For over a decade the Turos laboratory has been designing small molecules to target pathogenic microbes such as Staphylococcus aureus and the resistant variants like methicillin-resistant Staphylococcus aureus (MRSA). Previously, N-thiolated Β-lactams, N-thiolated 2-oxazolidinones and aromatic disulfides that were synthesized in Dr. Turos' lab have shown strong activity against these bacteria. The present work describes the synthesis and antimicrobial activities of a related structural class called S,S'-heterosubstituted disulfides. For ages, sulfur (elemental) has been used as an antibacterial for controlling infestation and bacterial …

Lead Discovery And Optimization Strategies Towards The Development Of 4(1h)-Quinolones And 1,2,3,4-Tetrahydroacridone Analogs With Antimalarial Activity, Richard Matthew Cross

USF Tampa Graduate Theses and Dissertations

The goal of our research endeavor was to successfully employ modern lead discovery and optimization strategies towards the development and identification of compounds possessing antimalarial activity. Preliminary data from in vitro screening at the Walter Reed Army Institute of Research identified several chemotypes including 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones to have potent antimalarial activities. Multiple synthetic routes were devised and implemented which enabled the rapid preparation and isolation of over 400 structurally diverse 4(1H)-quinolones and 1,2,3,4-tetrahydroacridones.

Our research towards discovering and optimizing antimalarials was inspired from the severe impact malaria has had on our planet especially on impoverished countries. There are over …

Chemical Investigation Of The Antarctic Marine Invertebrates Austrodoris Kerguelenensis & Dendrilla Membranosa And The Antarctic Red Alga Gigartina Skottsbergii, John Alan Maschek

USF Tampa Graduate Theses and Dissertations

The marine realm and, in particular, the Antarctic benthos is largely unexplored and understudied. The chemical investigation reported herein reveals not only the biodiversity, but how that biodiversity manifests remarkable chemical diversity. In our continuing study of the nudibranch Austrodoris kerguelenensis, we have isolated a diverse suite of diterpenoid glyceride esters, palmadorins D - S (2.32 - 2.47), one of which is the first reported halogenated diterpene from a dorid nudibranch. Utilizing genomic data from collaborators, we have investigated the chemical diversity from phylogenetically unique specimens collected in close proximity to one another. Chemical groupings based on comparison of LC/MS …