Copper-mediated alkyne-azide cycloadditions yield 1,4-disubstituted triazoles with high chemoselectivity that can be used in many ways. For instance, when alkyne or azido peptide units combine via this pathway the reaction is relatively insensitive to the amino acid side-chains. This serves as an excellent way to produce peptidomimetics, particularly because there is some stereoelectronic similarity between 1,2,3-triazoles and amide bonds. Linear peptidomimetic substrates 60 were used to form the cyclic derivatives 61 via copper catalyzed azide alkyne cycloadditions. This reaction is fast, simple to perform and compatible with many solvents and functional groups. A library of eight cyclic peptidomimetics was prepared in solution and the low yield was mostly due to formation of dimers. Computational, NMR, and CD analyses of compounds 61a-c indicate that their most favorable conformational states include type I and type II β-turn conformations. Monovalent triazole mimics were prepared via cycloaddition reactions in solution. These triazole compounds contain two amino acid chain functionalities at 1- and 4- positions. One is derived from a natural amino acid and the other is a functional group that resembles the side chains of an amino acid. The 1,3-dipolar cycloaddition reactions allow quick and efficient generation of the desired peptidomimetics in good yields. Two monovalent mimics were coupled to the linker scaffold sequentially in solution by simply manipulating the solvent systems. This method allows us to prepare large libraries of bivalent compounds quickly and efficiently. The two monomers were combined with each other cleanly, to achieve one-compound-per-well in sufficient purity for biological testing. Oxidative coupling to give 5,5’-bistriazoles is discussed. The bistriazole products predominate in the copper accelerated “click reaction” of alkynes and azides when carbonate bases are used as additives (ca 1 – 2 M). The reaction seems to be more efficient for propargylic ethers and less hindered substrates. Use of optically active azides could afford separable atropisomeric products, providing a convenient access into optically pure derivatives.

Tübingen, Univ., Diss., 2003.

Cette thèse se concentre sur le design et la synthèse de molécules fluorescentes contenant un motif triazole et un squelette benzothiadiazole (BTD), coumarine, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacène (BODIPY) ou dicyanométhylène-4H-pyran (DCM) par chimie "click" et l’étude de leurs propriétés et applications en biologie et en chimie analytique. Dans le but de synthétiser des peptides fluorescents et d'étudier leurs applications, des acides aminés fluorescents contenant BTD, coumarine et BODIPY ont été préparés par réaction "click", et incorporés dans la somatostatine par synthèse peptidique en phase solide. Les peptides fluorescents synthétisés pourront être utilisés pour le développement d'un test de "binding" des analogues de la somatostatine. Des dérivés de BTD et BODIPY ont également été conçus et synthétisés pour servir de mimes de coudes beta- qui conduisent à des peptides courts qui pourraient être facilement détectés et étudiés en utilisant des techniques de fluorescence. La capacité des composés obtenus à former des liaisons hydrogène intramoléculaires a été étudiée par spectroscopie infrarouge. En outre, une série de macrocycles à base de BODIPY contenant un C-glucopyranoside conjugué ou non à des acides aminés tels que glycine, acid aspartique ou méthionine ont été synthétisés avec succès en utilisant une réaction "click" comme étape de macrocyclisation. Certains des composés synthétisés présentent des propriétés de reconnaissance sélective vers Cu2+, Fe3+, F- et CN- dans l'acétonitrile. Enfin, un nouveau capteur fluorescent, qui est capable de reconnaître les cations et anions d'une manière coopérative, a été conçu et synthétisé par chimie "click". Ce composé est très sensible à des combinaisons de Cu2+, F- et / ou Br- d’une manière séquence- et halogénure-dépendante. / This thesis is focused on the design and synthesis of triazole-containing fluorescent molecules based on benzothiadiazole (BTD), coumarin, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) or dicyanomethylene-4H-pyran (DCM) by “click” chemistry and investigation of their properties and applications in biology and analytical chemistry. In the aim to synthesize fluorescent peptides and investigate their applications, fluorescent amino acids containing BTD, coumarin and BODIPY were prepared by “click” reaction, and incorporated into somatostatin through solid phase peptide synthesis. The resulting fluorescent peptides could be used for the development of a binding assay for somatostatin analogues. BTD and BODIPY derivatives have also been designed and synthesized to act as beta-turn mimics which lead to short conformationally restricted peptides that could be easily detected and studied using fluorescence techniques. The ability of the synthesized compounds to form intramolecular hydrogen bond was studied by infrared spectroscopy. Moreover, a series of BODIPY-based macrocycles containing a C-glucopyranoside conjugated or not with various amino acids such as glycine, aspartic acid or methionine have been successfully synthesized by using “click” reaction as the macrocyclization step. Some of the synthesized compounds exhibited selective recognition properties towards Cu2+, Fe3+, F- and CN- in acetonitrile. Finally, a new fluorescent sensor, which has the ability to recognize cations and anions in a cooperative way, was designed and synthesized by “click” chemistry. This compound was highly sensitive to combinations of Cu2+, F– and/or Br– in a sequence- and halide-dependent way.

Biofouling impedes the performance of membrane bioreactors. In this study, we investigated the antifouling effects of polysulfone membranes that were modified by 1,2,3-triazole and palladium nanoparticles. The membranes to be tested were embedded within a drip flow biofilm reactor, and Pseudomonas aeruginosa PAO1 was inoculated and allowed to establish biofilm on the tested membranes. It was found that 1,2,3-triazole and palladium nanoparticles can inhibit the bacterial growth in aerobic and anaerobic conditions. The decrease in bacterial growth was observed along with a decrease in the amount of total polysaccharide and Pel polysaccharide within the biofilm matrix but not the protein content.

The use of transition metals in synthesis is an incredibly useful tool for organic chemists. Co-ordination of a metal can occur with most function groups in some manner resultingin dramatic changes in the reactivity. Decarboxylative cross-couplings provide a new route to the construction of C–C bondswithout the necessity of costly organometallic precursors. Similarly C–H activationprovides an environmentally and economically desirable method to cross-couplingproducts, and this can be facilitated by the presence of ortho-directing groups. Thedecarboxylative coupling of carboxylic acids, combined with carboxylate directed C–Hactivation has been investigated to demonstrate ortho-arylation and acylation of benzoicacids. In doing so the different functionality of the carboxylate group is demonstrated inone process. Following this, a mild ZnEt2 mediated 1,5-substituted 1,2,3-triazole formation reactionhas been investigated. Significantly, this method is compatible with many differentsubstrates including halides, esters, nitriles, ketones and amides which have proven to beincompatible with analogous Mg or Li methods. The resultant heteroaryl zinc can beutilised further in cross-coupling reactions, or with other electrophiles, enabling theformation of a wide range of substituted triazoles.

Polymer mechanochemistry, wherein exogenous forces are harnessed to drive chemical processes within polymeric matrices, has afforded access to an astounding array of otherwise kinetically prohibitive reactivity. These multifarious mechanochemical transformations include formally symmetry forbidden electrocyclic processes, thermodynamically disfavored isomerizations, and thermally inaccessible cycloreversions of both carbocyclic and heterocyclic functionalities. The fundamental principles that govern mechanochemistry, however, remain elusive. To address this deficiency, we report a series of experimental and computational efforts that probe chemical reactivity under the action of mechanical force. Specifically, we have explored the formal 1,3-dipolar cycloreversion of 1,2,3-triazole moieties in an effort to understand the interplay between kinetic stability and mechanical perturbation. Briefly, 1,4-disubstituted 1,2,3-triazoles were embedded within high molecular weight poly(methyl acrylate) chains and reverted into their azide and terminal alkyne precursors sonochemically. The liberated azide and alkyne moieties were identified by orthogonal chemical ligation to chromophores, and the reactive azido- and alkynyl-polymer fragments could be recoupled through a copper-mediated cycloaddition. Inspired by this result, we developed a computational model to rapidly discover qualitative trends in mechanochemical reactivity. Application of this model to the cycloreversion of 1,2,3-triazoles revealed an intriguing result: the 1,5-disubstitued regioisomer was predicted to exhibit enhanced susceptibility to mechanical cycloreversion in comparison to the 1,4-disubstituted congener. This trend was experimentally verified upon embedding 1,5-disubstituted 1,2,3-triazoles into high molecular weight poly(methyl acrylate) chains and subjecting them to ultrasonication. Specifically, the observed rate constant for chain scission of a poly(methyl acrylate) material containing the 1,5-disubstituted isomer was 20% larger than that of an analogous material containing the 1,4-disubstituted congener. Having established confidence in the predictive capabilities of our model, we undertook an exhaustive evaluation of regiochemical effects on the activation of six previously reported mechanically labile scaffolds. Our theoretical work suggested that all of the evaluated scaffolds could exhibit suppressed reactivity under stress (an underexplored phenomenon), and this result was supported by experimental investigation. Moreover, our theoretical considerations predicted that anti-Hammond effects (i.e., increased structural dissimilarity between reactant and transition state geometries as the two approach energetically) could be predominant in mechanochemical processes. Finally, we endeavored to expand the scope of polymer mechanochemistry beyond traditional chemical systems to biologically relevant species. We found that the photophysical properties of fluorescent protein variants could be modulated by embedding the proteins within poly(methyl methacrylate) matrices and compressing the resulting composites. / text

Bimetallic complexes are known to have unique electronic properties and are used in a variety of organic transformations as catalysts. The use of naphthalene-bridged bis- triazoles (NBT) for bimetallic complexes is unknown. NBTs have the unique property of being fluorescent stemming from a twisted intramolecular charge transfer. With the non- coplanar geometry and the distance between the 1,2,3-triazole rings, we hypothesized that 1,8-bis(4-phenyl-2H-1,2,3-triazol-2-yl)naphthalene (12) would be a suitable ligand to synthesize a bimetallic complex. The synthesis of 12 was optimized for large scale synthesis and was synthesized on a 78 mmol scale in 15% total yield. Metal complexation trials were conducted on 12 and several insoluble solids were observed.

The genus Aspergillus possesses broad functionality and occupation of ecological niches. Underpinning this are changes in the transcriptome of these species. Transcriptional changes are clinically relevant with respect to understanding triazole resistant isolates of Aspergillus fumigatus. Reverse-transcription quantitative Polymerase Chain Reaction (RT-qPCR) is a highly specific means of measuring changes in gene expression. The most common method of which requires normalization to experimentally validated, stably expressed reference genes. Ideal reference genes are unaffected by differences in the experimental conditions or strains/isolates and are expressed at levels near the target gene(s). The first study reviewed current practices for reference gene selection and validation for RT-qPCR gene expression analysis of the genus, Aspergillus. Information on the species examined, experimental conditions, sample type, normalization strategy, reference gene(s) and their state of validation was obtained from 90 primary studies. Twenty reference genes were used, with the most popular reference genes used encoding beta-tubulin, actin, 18S rRNA and glyceraldehyde-3-phosphate dehydrogenase. Seventeen of the 90 studies experimentally validated the expression stability of the reference genes used, out of which eight used more than one reference gene. The results of three studies conflicted with others described in the literature, with no experimental validation of the reference genes available to aid in interpreting the conflicting findings. In the Genome-Wide Association Study, genes noted to increase in expression in response to itraconazole and/or voriconazole treatment of A. fumigatus were extracted from published RNA-sequencing or RT-qPCR studies. Ten ATP-binding cassette transporters, four major facilitator superfamily transporters and 16 transcription factors were identified. Collectively, the findings of this thesis show a large disparity in experimentally validated reference genes as well as future targets of gene expression analysis in triazole resistant isolates of A. fumigatus. / Thesis / Master of Science (MSc) / Aspergillus is a globally distributed genus of fungi, with some species threatening opportunistic human infection. To combat infection with the opportunistic species, Aspergillus fumigatus, antifungal drugs including: itraconazole, voriconazole and amphotericin B are used. Recent years have seen a rise in antifungal resistance in A. fumigatus. To understand this and other mechanisms in Aspergillus, changes in gene expression must be examined. My thesis aimed to determine how reference genes are selected for reverse-transcription quantitative polymerase chain reaction, a method applied to measure gene expression changes in Aspergillus. It was discovered that very few studies between the years 2001 and 2020 experimentally validated that the reference genes used were stably expressed, with only 17 out of 90 studies providing validation. In part two of my thesis, genes overexpressed in A. fumigatus when exposed to antifungal drugs, from formerly published articles, were summarized to better understand the role of gene expression in antifungal drug resistance.

No description available.

La ghréline, une hormone peptidique principalement synthétisée au niveau de l'estomac, est le ligand endogène du récepteur des sécrétagogues de l'hormone de croissance appelé GHS-R1a. Elle est impliquée dans de nombreux processus biologiques dont principalement la sécrétion de l'hormone de croissance et la régulation de l'homéostasie énergétique. En raison de ses propriétés orexigènes et adipogènes, la ghréline est un outil puissant pour lutter contre les déséquilibres énergétiques. Développer des antagonistes de son récepteur représente ainsi une stratégie prometteuse pour la découverte de nouvelles pharmacothérapies contre l'obésité.Cette thèse est consacrée au développement d'antagonistes du récepteur de la ghréline dont la structure est basée sur une plateforme peptidomimétique : le 1,2,4-triazole 3,4,5-trisubstitué. Notre objectif est de concilier au mieux l'affinité et l'activité de nos ligands vis-à-vis du GHS-R1a avec des propriétés optimisées permettant de favoriser une bonne biodisponibilité orale. Nous nous sommes basés sur une synthèse rapide et efficace de ces composés pour réaliser des études approfondies de relations structure-activité et structure-propriété. En optimisant successivement les différentes positions autour du motif triazole, des compromis intéressants ont été obtenus. Nous avons ainsi identifié des antagonistes affins du récepteur qui présentent une stabilité microsomale suffisante et une perméabilité membranaire satisfaisante pour envisager des études in vivo. / Ghrelin, a peptidic hormone which is mainly synthesized in the stomach, is the endogenous ligand of the growth hormone secretagogue receptor named GHS-R1a. It is involved in numerous biological processes such as the growth hormone secretion and the control of energy homeostasis. Because of its orexigenic and adipogenic properties, ghrelin is a potent tool to control energy imbalance. Developing ghrelin receptor antagonists represents a promising strategy for the discovery of anti-obesity new drugs.This thesis is devoted to the development of ghrelin receptor antagonists based on a peptidomimetic scaffold: the 3,4,5-trisubstituted 1,2,4-triazole. Our aim is to combine ligand affinity and activity towards GHS-R1a with optimized properties which enable to promote a good oral bioavailability. We based our work on a rapid and efficient synthesis of our compounds to carry out detailed structure-activity and structure-property studies. By successively optimizing the different positions around the triazole scaffold, interesting compounds were obtained. We have thus identified receptor antagonists which exhibit sufficient microsomal stability and satisfactory membrane permeability to consider in vivo studies.