Physical Sciences and Mathematics Commons^™

Development Of New Photochemical Tools For Applications In Cancer Research And Enzymatic Signaling, Nicholas Paul Toupin

Wayne State University Dissertations

Photochemical tools empower researchers to act with precision and control over the cellular environment through production of reactive oxygen species (ROS), targeted drug delivery, and modulation of enzymatic activity. These molecular tools use light as a readily available, biorthogonal reagent for initiating advantageous light-activated reactions. Using light in this way allows researchers to affect the cellular environment in specific ways with high spatio-temporal control. This dissertation focuses on expanding the applications of, mostly Ru(II)-based, photoactivated chemicals. Complexes of this type are able to act as photosensitizers in photodynamic therapy (PDT), as photocages (PCT), or as dual-action compounds capable of both …

Phenanthroline-Catalyzed 1,2-Cis Glycosylation: Scope And Mechanism, Jiayi Li

Wayne State University Dissertations

Phenanthroline, a rigid and planar organic compound with two fused pyridine rings, has been used as a powerful ligand for metals and a binding agent for DNA/RNA. We recently discovered that phenanthroline could be used as a nucleophilic catalyst to access high yielding and diastereoselective α-1,2-cis glycosides through the coupling of hydroxyl acceptors with α-glycosyl bromide donors. The utility of the phenanthroline catalysis is expanded to sterically hindered hydroxyl nucleophiles and chemoselective coupling of an alkyl hydroxyl group in the presence of a free C1-hemiacetal functionality. In addition, the phenanthroline-based catalyst has a pronounced effect on site-selective couplings of triol …

Influence Of Conformational Restriction On The Antibacterial Activity And Ribosomal Selectivity Of Aminoglycoside Antibiotics, Michael Gabriel Pirrone

Wayne State University Dissertations

The ever-increasing threat posed by multidrug-resistant infectious bacteria necessitates

the development of novel antibiotics. Aminoglycoside antibiotics are growing in interest due to

their broad spectrum of activity, lack of known drug related allergies, low manufacturing cost,

and their well-studied mechanism of action. The simplification of rational drug design due to the

well-studied mechanism of action is the key to overcoming the issues presented by these drugs,

namely ototoxicity and nephrotoxicity.

A study of the effect of the conformation of the aminoglycoside ring I side chain is

described wherein it was discovered that an increase in a particular conformation augments the …

Exploring The Scope And Limitations Of The Oxidative Deamination Of N-Acetyl Neuraminic Acid, Mohammed Bakr Hawsawi

Wayne State University Dissertations

Sialic acids are molecules of importance in the fields of carbohydrate chemistry and glycoscience, and their diversity make them even more attractive to scientific research. Modifications of sialic acid derivatives may lead to several biological and chemical features that can be utilized for medicinal purposes. The modern drug therapy is dependent on the chemical discoveries of potent and effective molecules. N-Acetyl neuraminic acid is the parent and most common molecule in sialic acid family that received considerable attention in glycochemical research. This dissertation explores the scope as well as the limitations of the Zbiral oxidative deamination of N-acetyl neuraminic acid …

Synthesis Of Bradyrhizose And The Equatorial Glycosides Of 3-Deoxygenation-D-Mango-Oct-2-Ulosonic Acid, Philemon O. Ngoje

Wayne State University Dissertations

ABSTRACT

SYNTHESIS OF BRADYRHIZOSE AND THE EQUATORIAL GLYCOSIDES OF 3- DEOXY-D-MANNO-OCT-2-ULOSONIC ACID

Chapter one provides a general view on the background to the research in two parts. The first part begins with an introduction on the significance of the lectin-carbohydrate interactions in leguminous plants. Then the structure and role of O-antigen lipopolysaccharides in the symbiotic nitrogen cycle, and the mechanism and significance of the cycle in leguminous plants growth are introduced. The role, isolation and characterization of bradyrhizose are also introduced; and the previous syntheses of bradyhizose and of related bicyclic compounds presented.

The second part of chapter one starts …

Development And Application Of Chemical Tools To Identify Kinase-Substrate Interactions, Aparni Kithulgoda Gamage

Wayne State University Dissertations

Post translational modifications regulate a variety of biological processes inside the cell.Protein phosphorylation is one such PTM modification catalyzed by protein kinases, which aid to transfer a signal from one place to another inside the cell. However, irregularities in kinase-mediated signaling are often implicated in many diseases, making kinases effective drug targets. To understand kinase-related disease formation and to discover drugs to treat these diseases, it is crucial to have a clear understanding on kinase-mediated cell signaling networks. A current gap in the kinase biology field is a lack of tools to identify which kinase phosphorylates which protein substrate inside …

Influence Of Side Chain Conformation On The Mechanism(S) Of Glycosylation Reactions; Investigation Of Sialidation Reaction Mechanism(S) By Kinetic Studies, Harsha Chandhana Amarasekara

Wayne State University Dissertations

Glycosylation, being the key reaction of glycobiology and carbohydrate chemistry, demands robust and stereoselective glycosylation methods. The rational development of such methods necessitates knowledge of the glycosylation reaction mechanism and the factors influencing glycosylation reactions. The work discussed in this dissertation is focused on studying glycosylation reaction mechanisms and exploring the key factors influencing them.

Chapter one reviews the background to the research, starting with a brief introduction of the significance of carbohydrates as structural and energy-storage materials. The significance of cell surface carbohydrates and their roles in communication and related processes are discussed along with examples of their applications …

Harnessing The Reactivity Of The N-Methyl Diaminobenzoyl Linker To Access C-Terminally Modified And Macrocyclic Peptides, Christine Arbour

Wayne State University Dissertations

This thesis describes the exploration of accessing C-terminally modified and macrocyclic peptides through N-acyl urea (MeNbz) displacement. Prior to this work, the diaminobenzoyl linker was used to access thioesters for native chemical ligation. Only solution-phase displacement of the N-acyl urea with thiol nucleophiles was previously reported.

The N-Me-diaminobenzoyl (MeDbz) linker was initially used to access C-terminal glycine esters, amides, and acids from a single peptide substrate. This led to the total synthesis of Conopressin G and two analogs. The propensity of the C-terminal cysteine residue to undergo epimerization was investigated using this strategy. After optimization, C-terminal cysteine esters, amides, and …

Design Of Ruthenium(Ii) Polypyridyl Complexes For Effectively Caging Nitriles And Aromatic Heterocycles, Ao Li

Wayne State University Dissertations

ABSTRACT

DESIGN OF RUTHENIUM(II) POLYPYRIDYL COMPLEXES FOR EFFECTIVELY CAGING NITRILES

AND AROMATIC HETEROCYCLES

by

AO LI

May 2018

Advisor: Dr. Jeremy Kodanko

Major: Chemistry

Degree: Doctor of Philosophy

Ru(II) polypyridyl complexes have been frequently employed in the caging and photorelease of biologically active compounds. Traditional photocaging groups derived from Ru(II) have been largely based on bi- or tridentate ancillary ligands, and those bearing ancillary ligands with high-denticities are yet to be developed. Exploring Ru(II) polypyridyl complexes possessing ancillary ligands with high-denticities provides insight into the photophysical and photochemical properties of ruthenium complexes, which creates novel prospects in the design of …

Design And Synthesis Of Oligo-(3,5-Dithio-Β-D-Glucopyranoside) As Β-(1→3)-Glucan Mimetics, Xiaoxiao Liao

Wayne State University Dissertations

This dissertation presents the design and synthesis of oligo-(3,5-dithio-β-D-glucopyranoside) as β-(1 → 3)-D-glucan mimetics. The synthesized dimeric, trimeric and tetrameric mimetics were tested for their binding affinities to Dectin-1 and CR3 and their abilities to activate phagocytosis and pinocytosis.

The first chapter gives an introduction of β-(1 → 3)-D-glucan. It gives an introduction about the structure and origin of β-(1 → 3)-D-glucan as well as the immunostimulating effect of natural β-(1 → 3)-D-glucan. The study of interaction between β-(1 → 3)-D-glucan and the receptors leads to a conclusion that the hydrophobicity of β-(1 → 3)-D-glucan is crucial to its immunostimulating …

Modification Of 4,5- Aminoglycosides To Overcome Drug Resistance Bacteria And Toxic Side Effect, Guanyu Yang

Wayne State University Dissertations

ABSTRACT

MODIFICATION OF 4,5- AMINOGLYCOSIDES TO OVERCOME DRUG RESISTANCE BACTERIA AND TOXIC SIDE EFFECT

by

Guanyu Yang

September 2018

Advisor: Professor David Crich

Major: Chemistry

Degree: Doctor of Philosophy

Infectious diseases causing by antibiotic resistant pathogen are one of the major threat to human health and society today. Many researchers tried to develop next generation of antibiotics by reinvesting the existing antibacterial drugs. Aminoglycosides have long been used as highly potent and broad-spectrum antibiotics for treating bacterial infections. But their side effect, especially the irreversible ototoxicity, and the fast-growing resistant problem limit their application. The goal of this research was …

Stereoselective Synthesis Of Legionaminic Acid And Pseudaminic Acid Glycosides, Bibek Dhakal

Wayne State University Dissertations

Legionaminic acid (Leg) and pseudaminic acid (Pse) are deoxy acetamido analogues of the most common sialic acid, N-acetylneuraminic acid (NeuAc) that are found in microorganisms. Leg and Pse are rare but important class of sialic acids, as their glycosides are found in lipopolysaccharides and glycoproteins of several pathogenic Gram-negative bacteria including Pseudomonas aeruginosa, Legionella pneumophila serogroup 1, Campylobacter jejuni, and Campylobacter coli. As such, the stereoselective glycosylation of the equatorial Leg and Pse donors, and the role played by their side chain conformations in anomeric reactivity and selectivity are the focus of this thesis.

Chapter two describes the synthesis of …

Addressing The Threat Of Multidrug Resistant Infectious Diseases By Synthesis Of Novel Aminoglycoside Antibiotics, Girish Chandra Sati

Wayne State University Dissertations

The ever-growing increase in multidrug resistant infectious diseases is one of the major cause of human mortality, and there is an inherent need for the development of new antibiotics. Since the discovery of streptomycin, AGAs have been playing a very important role in human therapy as highly potent broad-spectrum antibiotics and are listed as one of the critically important antimicrobials by WHO. AGAs act by inhibiting the bacterial protein synthesis and by targeting the A-site present in the small subunit of bacterial ribosome. The clinical use of AGAs is somewhat restricted due to their toxic effects (ototoxicity and nephrotoxicity) and …

Cation Clock Reactions For The Determination Of Relative Reaction Kinetics In Glycosylation Reactions, Philip Adero

Wayne State University Dissertations

This dissertation presents the development of cyclization reactions as clocks for the determination of the molecularity of glycosylation reactions in individual pyranoside systems and extends it to the arabinofuranoside systems. It also describes the development of selective hydrogenolytic cleavage of naphthylmethyl ethers in the presence of sulfides.

The first part of chapter one gives an overview of the significance of glycochemistry and the challenges involved. The second part describes some selected glycosylation methods and extends this to the general mechanistic studies of glycosylation. This is followed by the discussion of the general clock reactions in literature which initiates a further …

Progress Toward Controlled Disulfide Formation To Access Neuroactive Conotoxins, Thilini Kondasinghe

Wayne State University Dissertations

"Conotoxins are mini proteins isolated from marine snails of the Conus family. They have shown activity in the selective inhibition of various ion channels. Therefore, they present an opportunity as possible therapy for a myriad of neurological ailments. The synthesis of conotoxins would enable both biological studies and evaluation of these structures as lead targets for therapeutics. However, establishing a reliable method to consistently folding disulfide rich proteins, including conotoxin, into their native structure has been challenging over few decades. In this research project, it is shown the progress towards a mild, efficient, and broadly applicable methods to generate the …

Harnessing Radical Reactivity For The Construction Of Natural Product Frameworks And Transition Metal Catalyst Stability In A Modified Kochi Coupling Reaction, Mathes Hewage Hansamali Sakuntala Sirinimal

Wayne State University Dissertations

Polycyclic N-containing heterocycles play an important role in therapeutic

applications and as molecular tools in studying biological processes, making them

important synthetic targets. Current synthetic approaches are too lengthy, use toxic

reagents or are limited to accessing a particular framework and hence, their synthesis

warrant further study. We have recently developed conditions to avoid both reduction and

slow addition in aminyl radical cyclizations in our venture to access the constrained ABC

core of calyciphilline A, a Daphniphyllum alkaloid. An electron deficient enone with a

pendent internal alkyne as the neutral aminyl radical precursor was used for radical

cyclization. Based on …

Design, Synthesis And Analysis Of Potential Photo-Activatable Cathepsin K Inhibitors, Khalin Evania Nisbett

Wayne State University Theses

Abstract

DESIGN, SYNTHESIS AND ANALYSIS OF POTENTIAL PHOTO-ACTIVATABLE CATHEPSIN K INHIBITORS

by

KHALIN NISBETT

May 2017

Advisor: Dr. Jeremy Kodanko

Major: Chemistry

Degree: Master of Science

Tightly regulated cysteine CA proteases play a major role in maintaining the homeostasis within cells. Subsequently, when these proteases are dysregulated and mislocalized they disrupt healthy cell dynamics and contribute to many life-threatening pathologies such arteriosclerosis, osteoporosis and cancer. As such many pharmaceutical companies and research teams are highly interested in these proteases as targets. One emergent strategy is the spatiotemporal control of biological processes. In relation to this, a series of spatiotemporally controlled …

Design, Synthesis And Biological Evaluation Of Histone Deacetylase (Hdac) Inhibitors: Saha (Vorinostat) Analogs And Biaryl Indolyl Benzamide Inhibitors Display Isoform Selectivity, Ahmed Negmeldin

Wayne State University Dissertations

HDAC proteins have emerged as interesting targets for anti-cancer drugs due to their involvement in cancers, as well as several other diseases. Several HDAC inhibitors have been approved by the FDA as anti-cancer drugs, including SAHA (suberoylanilide hydroxamic acid, Vorinostat). Unfortunately, SAHA inhibits most HDAC isoforms, which limit its use as a pharmacological tool and may lead to side effects in the clinic. In this work we were interested in developing isoform selective HDAC inhibitors, which may decrease or eliminate the side effects associated with non-selective inhibitors treatment. In addition, isoform selective HDAC inhibitors can be used as biological tools …

Synthesis Of Netilmicin And Apramycin Derivatives For The Treatment Of Multidrug-Resistant Infectious Diseases, Amr Sayed Motawi Sonousi

Wayne State University Dissertations

The ever-growing bacterial resistance to existing antibiotics is alarming to humanity. Many researchers decided to revisit aminoglycosides with renewed emphasis on chemical modification as they have long been used as highly potent antibiotics for treating severe bacterial infections. The bactericidal effect of aminoglycosides is mainly due to protein synthesis inhibition by binding to the A-site of the bacterial ribosomes. However, the high potency and the broad spectrum of aminoglycosides has been outweighed by their side effects, especially ototoxicity, and by the resistance of pathogens. The goal of this research was the modification of existing aminoglycosides to develop derivatives which are …

Development Of Gamma-Modified Atp Analogs To Study Kinase-Catalyzed Phosphorylations, Ahmed Eid Fouda

Wayne State University Dissertations

Kinase-catalyzed protein phosphorylation is one of the most important post-translational modifications that controls cascades of biochemical reactions. Irregularities in phosphorylation result in many diseases, such as diabetes mellitus, Parkinsons, and cancer. The development of new methods to monitor kinase-catalyzed phosphorylation is needed to decipher details of normal and diseased cell signaling. The Pflum lab recently developed several -modified ATP analogs to study kinase catalyzed phosphorylation reactions. The -modified ATP analogs have different tags, such as biotin for substrate labeling or aryl-azide for kinase substrates identification. Unfortunately, use of -modified ATP analogs was limited to in vitro studies due to the …

Facile Synthesis Of Tertiary Aliphatic Amine– Containing Cyclic Motif Via Neutral Aminyl Radical Cyclization, Heng Chen

Wayne State University Theses

Tertiary amine–containing cyclic motifs are prevalent in natural products and pharmaceutical lead targets. Inspired by these biological active molecules, one focus in our lab is the development of neutral aminyl radical chemistry in the synthesis of tertiary aliphatic amine–containing cyclic compounds. In this project, I investigated the mono- and tandem cyclization of aminyl radical with different types of olefins (terminal olefin, enone, and styrenyl). The effect of the hydrogen atom donor and the limitation of the reaction will be discussed.

Synthesis Of Apramycin And Paromomycin Derivatives As Potential Next Generation Aminoglycoside Antibiotics And Chemistry Of Isothiocyanato Sialyl Donors, Appi Reddy Mandhapati

Wayne State University Dissertations

AGAs are clinically important antibacterials for human therapy and have long been used as highly potent antibiotics for treating several bacterial infections. The fidelity of protein synthesis is affected by AGAs in the course of binding to specific sites of the bacterial rRNA. The clinical use of AGAs and their applications as therapeutics is restricted by toxicity (irreversible ototoxicity and reversible nephrotoxicity) and by the resistance of pathogens. The objective of this research was the development of proficient AGAs that are less toxic (i.e., more selective) and that evade resistance. The first three chapters of this thesis are aimed towards …

Synthesis, Characterization, And Properties Of Peroxo-Based Oxygen-Rich Compounds For Potential Use As Greener High Energy Density Materials, Nipuni-Dhanesha Horadugoda Gamage

Wayne State University Dissertations

One main aspect of high energy density material (HEDM) design is to obtain greener alternatives for HEDMs that produce toxic byproducts. Primary explosives lead azide, lead styphnate, and mercury fulminate contain heavy metals that cause heavy metal poisoning. Leaching of the widely used tertiary explosive NH4ClO4 into groundwater has resulted in human exposure to ClO4– ions, which cause disruptions of thyroid related metabolic pathways and even thyroid cancer. Many research efforts to find replacements have gained little success. Thus, there is a need for greener HEDMs. Peroxo-based oxygen-rich compounds are proposed as a potential new class of greener HEDMs due …

Studying The Atp Cosubstrate Promiscuity Of Nucleotide And Lipid Kinases, Thilani Murium Anthony

Wayne State University Dissertations

The kinase family consist of a large assortment of enzymes that phosphorylate a variety of substrates, including proteins, nucleosides, polynucleotides, lipids, sugars, and other small molecules. The Pflum lab recently found that protein kinases promiscuously accept an ATP analog containing a biotin at the γ-phosphate (ATP-biotin) as a cosubstrate to label the hydroxyl side chains of Ser, Thr and Tyr residues with biotin. The main goal of this new project is to extend the use of kinase-catalyzed biotinylation towards polynucleotides. Crystallographic studies of T4 polynucleotide kinase (T4 PNK) that phosphorylates the 5’-hydroxyl termini of DNA and RNA show a solvent …

Design And Synthesis Of Isatin-Based Caspase Inhibitors For Ruthenium Caging Applications, Kasun Chinthaka Ratnayake

Wayne State University Theses

ABSTRACT

DESIGN AND SYNTHESIS OF ISATIN BASED CASPASE INHIBITORS FOR RUTHENIUM CAGING APPLICATIONS

by

KASUN CHINTHAKA RATNAYAKE

August 2015

Advisor: Jeremy J. Kodanko, Ph.D.

Major: Chemistry (Organic)

Degree: Master of Science

Apoptosis is the energy dependent programmed cell death. Improper function of apoptosis could lead to diseases such as cancers, strokes, Alziemer’s disease. Caspases are the enzymes involved in the later stage of this process. Peptidyl and non-peptidyl caspase inhibitors have been synthesized recently. These non-peptidyl compound classes which consist of pyrrolidinyl-5-sulfo isatins have showed a greater potency against executioner caspases, caspase-3 and -7. According to literature and for further …

New Carbohydrate-Based Anti-Cancer And Anti-Bacterial Vaccines, Zhifang Zhou

Wayne State University Dissertations

The unique carbohydrates expressed on the surface of cancer, bacterial, viral and fungal cells are excellent target antigens for the design of therapeutic or preventive vaccines. However, as antigens carbohydrates have problems. First, carbohydrates usually have low immunogenicity. Second, even if immunogenic, carbohydrates typically elicit T cell-independent immune responses. To overcome these problems and design useful vaccines based on carbohydrate antigens, they are usually coupled with carrier proteins to form conjugates to enhance the immunogenicity of the antigens. However, there are still some issues existing in glycoprotein vaccines, such as poor reproducibility of the conjugates, difficulties in quality control and …

1. Chromium(0)- Promoted Higher Order Cycloaddition Reactions: Studies Toward The Total Synthesis Of The Cyclocitrinols And Echinopines A And B 2. Total Synthesis Of (±)-Debromoflustramine B Via [4+1] Cyclization Of An Indole Isocyanate And A Bis(Alkylthio)Carbene, Saptarshi De

Wayne State University Dissertations

A facile and short stereoselective synthesis of the functionalized tetracyclic core structure of the cyclocitrinols, a family of unusual C25 steroid isomers, has been accomplished. The key structural unit, the bicyclo[4.4.1]A/B ring system, was constructed by a regioselective Cr(0)-promoted [6π + 4π] photochemical cycloaddition reaction.

A Bronsted acid catalyzed rearrangement of the 11-trimethylsilyl-tetracyclo[8.1.0.03,7.04,11]undeca-5,8-diene ring system to the unusual homotriquinacene ring system. The trimethylsilyl substitution on the cyclopropane moiety was found to be crucial for the rapid transformation which is believed to proceed via carbocation intermediates.

A short concise formal synthesis of Echinopines A and B is reported. The key [5.5.7] …

Synthesis And Application Of Atp Analogs For Phosphorylation-Dependent Kinase-Substrate Crosslinking, Satish Kumar Garre Venkata Raghavendra

Wayne State University Dissertations

Phosphorylation is an important post-translational modification that plays a key role in a variety of signaling cascades and cellular functions. Kinases phosphorylate protein substrates in a highly regulated manner and are promiscuous. Understanding kinase-substrate specificity has been challenging and there is a need for new chemical tools. To this end we developed -phosphate modified ATP photocrosslinking analogs ATP-ArN3 and ATP-BP, that crosslink substrate and kinase in a phosphorylation dependent manner. We have successfully demonstrated that ATP-ArN3 and ATP-BP can be used with natural kinase and substrates using cell lysates in vitro. We used our approach to identify novel kinases of …

Synthesis Of Oligosaccharide Mimetics By The Desulfurative Rearrangement Of Allylic Disulfides And Stereoelectronic Influence Of C-O Bonds On C- And O-Glycosylation, Myriame Moume-Pymbock

Wayne State University Dissertations

This dissertation focuses on two different problems. The first part of this manuscript presents the application of a novel methodology to access the synthesis of oligosaccharide mimetics while the second part focuses on the study of the stereoelectronic effects of proximal C-O bonds in C- and O-glycosylation reactions.

The first chapter provides a brief overview of the important roles that oligosaccharides and glycoconjugates play in biological processes and sets out the major advances that have been made in the past few decades in the synthesis of such complex structures while bringing out the ongoing challenges and the limitations that impede …

Chemical Synthesis Of Peptides And Peptide Thioesters, Indrajeet Sharma

Wayne State University Dissertations

This dissertation describes investigations toward the development of a new chemistry for the block synthesis of peptides and peptidyl thioesters. A direct approach for the Fmoc-SPPS of peptidyl thioesters is also delineated in this thesis.

In the first part of chapter one, the difficulty and importance of chemical synthesis of peptides is explained, and a brief survey of available methods is given. The second part of chapter one presents the challenges inherent in the synthesis of peptidyl thioesters by Fmoc-SPPS.

The second chapter outlines the investigations conducted towards the development of a new chemistry for epimerization-free block synthesis of peptides …