1,721,019 research outputs found
Radical Mediated Decarboxylation of Amino Acids via Photochemical Carbonyl Sulfide (COS) Elimination
Full text linkHerein, we present the first examples of amino acid decarboxylation via photochemically activated carbonyl sulfide (COS) elimination of the corresponding thioacids. This method offers a mild approach for the decarboxylation of amino acids, furnishing N-alkyl amino derivatives. The methodology was compatible with amino acids displaying both polar and hydrophobic sidechains and was tolerant towards widely used amino acid-protecting groups. The compatibility of the reaction with continuous-flow conditions demonstrates the scalability of the process
Synthesis and biological evaluation of mycobacterium tuberculosis derived glyconjugates and glycosylated nanoparticles
No full textThis thesis is entitled \u27Synthesis and biological evaluation of Mycobacterium tuberculosis derived glycoconjugates and glycosylated nanoparticles\u27 and is composed of 6 chapters. Chapter 1 begins with an overview of the biology of Mycobacterium tuberculosis (M. tb), the causative agent of the disease Tuberculosis (TB). Its effect on the host immune system and the current treatments available for the disease are covered. The next section details the role of phenolic glycolipids (PGLs) and the related glycans, the para-hydroxybenzoic acid derivatives (p-HBADs) in M. tb infection, followed by their biosynthesis and previously reported syntheses of these glycans. Following this, the successful application of carbohydrate-based vaccines is covered, along with significant advancements in the development of carbohydrate-based nanoparticle vaccine candidates. The next section introduces the trehalose disaccharide and its role in M. tb infection. Particular emphasis is placed on the synthesis of unnatural trehalose derivatives for employment in numerous biological applications. The final section provides a summary of the concept of carbohydrate based enzymatic probes for the detection of glycosidase enzymes. Following this, some recent examples of nanoparticle based probes are outlined, prior to a brief discussion of the detection of the trehalase enzyme. This chapter concludes with an overview of the work presented within this thesis. The first part of this work, comprising of Chapters 2 and 3, details the development of p-HBAD functionalised gold nanoparticles (AuNPs) as potential vaccine candidates for M. tb. Chapter 2 begins with a discussion of key concepts in the chemical synthesis of carbohydrates. Subsequently, this chapter focuses on the synthesis of the p-HBAD glycans and related glycoconjugates suitable for AuNP conjugation. The synthetic approach utilised for the preparation of these glycoconjugates involves the use of multiple protecting group manipulations and optimisation of glycosylation conditions to achieve the native methylation patterns and stereochemistry of the anomeric positions of the p-HBAD glycans. Chapter 3 begins with a summary of previous work reported on the immunomodulatory activities of the p-HBAD glycans, followed by a brief introduction into the employment of AuNPs for biological applications. The investigation into the immunomodulatory effect of the p-HBAD glycoconjugates, synthesised in Chapter 2, on murine cytokine production is also presented. Subsequently, the synthesis of p-HBAD functionalised AuNPs, which was carried out by Dr. Finn Purcell-Milton and Prof. Yurii Gun?ko in the School of Chemistry, TCD is briefly discussed. Finally, preliminary investigations into the biological evaluation of the p-HBAD functionalised AuNPs is detailed. The second part of this work, covered in Chapter 4, outlines the use of trehalose functionalised quantum dots (QDs) for the development of a fluorescent enzyme sensor for detection of trehalase activity. This chapter begins with a brief overview of QDs and their utilisation as nanoprobes for the detection of enzymatic activity. Following this, the design, synthesis, evolution and optimisation of a library of trehalose derivatives suitable for QD functionalised is discussed. Subsequently, the QD functionalisation, carried out by Vera Kuznetsova, Anastasia Visheratina and Prof. Yurii Gun?ko in the School of Chemistry, TCD, is briefly discussed. This chapter concludes with the preliminary evaluation of the ability of the trehalose functionalised QDs to serve as fluorescent probes for observing trehalase activity. Chapter 5 concludes the work described in this thesis and outlines future work. Lastly, Chapter 6 details the procedures used for the cellular studies, experimental procedures and characterisation of all compounds prepared within this thesis
The development of radical methodologies for the syntehsis of thiolactones and carbon-sulfer bond formation
No full textThis thesis entitled "The Development of Radical Methodologies for the Synthesis of Thiolactones and Carbon-Sulfur Bond Formation" is divided into 7 chapters in which Chapter 1, the introduction, presents an overview of the thiol-ene and thiol-yne reaction, in particular in an intramolecular context. It also provides a short review of the methods currently available for the synthesis of thiolactones, a fascinating class of compound with far-reaching applications from medicinal chemistry to materials science. Chapter 2 discusses our unsuccessful efforts at developing a thio-Dénès-modified Ueno-Stork cyclization for the synthesis of γ-thiolactones. However, this chapter does contain the first example of the direct radical cyclization of an α-bromo allylic thioester. In Chapter 3 the development of a methodology for the direct radical cyclization of thioacids onto alkenes and alkynes for the synthesis γ-thiolactones is reported. We introduce the acyl thiol-ene (ATE) and acyl thiol-yne (ATY) terminology and expand on the importance of distinguishing these reactions from their non-acyl analogues with support from computational studies of the ATE cyclization reaction. Divulged in Chapter 4 is a strategy for the synthesis of δ-thiolactones based on the ATE reaction of γ-alkenyl esters followed by Steglich thiolactonization. γ-Alkenyl esters may also be converted to γ-thiolactone, thus allowing for divergent approach to both compound classes. Chapter 5 exploits atmospheric oxygen as an initiator for the intermolecular thiol-ene reaction, proving capable of generating thiyl radicals from thioacids, alkanethiols and thiophenols to generate a plethora of robust thioester and thioether linkages. In this chapter we report our optimization of this reaction process and conduct a concise mechanistic study which validates our proposed radical mechanism. Furthermore, we also conduct a near exhaustive examination of the scope of this reaction in terms of functional group compatability. Chapter 6 gives overall conclusions on the results and methodological advancements obtained from the previous chapters. Finally, Chapter 7 comprises the experimental procedures for the synthesis of all the compounds described in the previous chapters, as well as the methods used for the different techniques employed
The synthesis, photophysical and biological evaluation of glycosylated naphthalimides for medicinal and material applications
No full textThis thesis entitled ?Synthesis, Photophysical and Biological Evaluation of Glycosylated Naphthalimides for Medicinal and Materials Applications? is divided into 8 chapters, in which Chapter 1, the introduction, gives an overview of the importance of carbohydrates in biology and for prodrug development as well as their use to improve site-selectivity and water solubility. It also explains what glycosidase enzymes are and how they have been used for prodrugs development. A short review on the photophysical and biological applications of naphthalimides, and some previous examples of glycosylated naphthalimides that can be found in the literature are also included. In Chapter 2, the synthesis of a family of glycosylated naphthalimides is described and their spectroscopic and biological properties examined. It was demonstrated that these compounds are good substrates for enzymatic (glycosidase) activity, which cleaves the carbohydrate moiety releasing the naphthalimide core. Interestingly, it was found that when the glycosylated compounds were incubated in vitro (in HeLa cells), no cell uptake occurs. However, the successful implementation of the enzymatic reaction (releasing the naphthalimide core) in vitro, allowed naphthalimide core to rapidly into the cells. Thus, Chapter 2 describes the development of a new class of compounds with interesting photophysical properties that via enzymatic release, could be used for the delivery of a probe inside the cells. Chapter 3 exploits the results obtained in Chapter 2 and aims for the use of this enzymatic-dependent release to deliver selectively (inside or outside the cell) a naphthalimide containing an alkyne group that could undergo click chemistry with modified sugars containing an azide group. These modified sugars, previously fed into the cells, can be metabolically incorporated into the cells? glycome. Interestingly, these compounds (when released by enzymatic exposure) were able to go into the cell nuclei, thus allowing for click chemistry with modified DNA bases as well. In Chapter 4, the enzymatic-dependent delivery is used in order to deliver a known cytotoxic drug (Amonafide). Thus, Chapter 4 comprises the synthesis, photophysical and biological evaluation of two compounds that could act as prodrugs of Amonafide, as an efficient delivery of Amonafide in vitro was demonstrated in three different cell lines as well as the cytotoxicity induced by the delivery of Amonafide. Chapter 5 describes the use of glycosylated naphthalimides as protein-binding probes, and the affinity of two glycosylated naphthalimides, one being a Tr?ger?s base of the other one, was successfully assessed using the lectin Concanavalin A (Con A). The changes in the fluorescence emission intensity demonstrated that the binding between the glycosylated naphthalimides and the protein was occurring. The binding with similar proteins is also investigated. Chapter 6 gives a brief description of the different self-assembled structures observed for these glycosylated naphthalimides, which range from microspheres to gels, and studies these different morphologies using confocal microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Chapter 6 gives an overview on the material side of these compounds, and how they could be relevant for different medicinal applications. Chapter 7 gives overall conclusions on glycosylated naphthalimides based on the results obtained from the previous chapters. Finally, Chapter 8 comprises the experimental procedures for the synthesis of the glycosylated naphthalimides described in the previous chapters, as well as the methods used for the different techniques employed
Supramolecular anion recognition mediates one-pot synthesis of 3-amino-[1,2,4]-triazolo pyridines from thiosemicarbazides
No full textA facile one-pot synthesis of 3-amino-[1,2,4]-triazolo[4,3-a]pyridines from thiosemicarbazides through anion mediated synthesis is reported. Thiosemicarbazides derived from 2-hydrazino pyridine, 5-chloro 2-hydrazino pyridine, and 2-hydrazine quinoline were formed in situ as anion receptors in the presence of TBAF. Under microwave heating, thiosemicarbazides furnished the triazolo pyridines in good to moderate yields. The formation of the thiosemicarbazides hydrogen bonding anion receptors was critical in cascading the reaction toward the formation of the triazolo pyridines
The synthesis and biological evaluation of Mycobacterium tuberculosis associated glycan derivatives
No full textTHESIS 10706Mycobacterium tuberculosis establishes chronic infection and causes disease through manipulation of the host\u27s innate and adaptive immune response. The bacterial cell wall is highly complex and contains a rich variety of glycosylated compounds, some of which are secreted during infection and have been proposed as immunomodulatory molecules. Amongst the most important of these are the p-hydroxybenzoic acid derivatives (p-HBADs) and phenolic glycolipids (PGLs). Herein is reported a synthetic methodology for the synthesis of these important biomolecules and their unnatural analogues and also the first in vitro study of the immunomodulatory effects of p-HBADs in isolation from the host bacterium
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Multi-Functionalized Carbon Nano-onions as Imaging Probes for Cancer Cells
Full text linkCarbon-based nanomaterials have attracted much interest during the last decade for biomedical applications. Multimodal imaging probes based on carbon nano-onions (CNOs) have emerged as a platform for bioimaging because of their cell-penetration properties and minimal systemic toxicity. Here, we describe the covalent functionalization of CNOs with fluorescein and folic acid moieties for both imaging and targeting cancer cells. The modified CNOs display high brightness and photostability in aqueous solutions and their selective and rapid uptake in two different cancer cell lines without significant cytotoxicity was demonstrated. The localization of the functionalized CNOs in late-endosomes cell compartments was revealed by a correlative approach with confocal and transmission electron microscopy. Understanding the biological response of functionalized CNOs with the capability to target cancer cells and localize the nanoparticles in the cellular environment, will pave the way for the development of a new generation of imaging probes for future biomedical studies
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