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Our group recently discovered and developed a diastereoselective reaction yielding C3-quaternary indolenines from the combination of α,β-unsaturated N-aryl ketonitrones and mono- or di-activated alkynes in toluene at 80 °C. This reaction builds a high level of complexity in a single step, and the C3-quaternary indolenines produced show promise as precursors to indole-containing molecules of biological and medicinal interest. However, we found our substrate scope was limited by the methods available for the synthesis of the α,β-unsaturated N-aryl ketonitrones necessary for the reaction. As a result of this need, we sought to develop a new way to access these α,β-unsaturated N-aryl ketonitrones. Our priorities were to develop a method that was expedient with regard to time and number of steps, modular, general, and could rely on inexpensive commercially available starting materials. The method that we have reported proceeds in three steps: starting with a commercially available aniline derivative and α,β-unsaturated aldehyde an imine is synthesized and alkylated using an organolithium reagent. The resultant secondary amine is then oxidized using Oxone® to obtain the α,β-unsaturated N-aryl ketonitrone. Only the nitrone is subject to a discrete purification step, and it can generally be isolated in yields of 50-80%. Unfortunately, the nitrones generated using this technique would not react with activated alkynes to yield indolenines. The two techniques discussed herein offer valuable insight into a poorly understood area of nitrone reactivity and are both synthetically useful in their own right. The studies performed make it clear that nitrones are a very viable synthetic intermediate; many nitrones can be easily accessed and then used to create very complex molecules in a diastereoselective manner. Both of these synthetic techniques in combination offer a valuable alternative approach to many complex and biologically interesting indole containing alkaloids. It is hoped that this work will serve as fertile ground for further studies towards increasing the utility of this chemistry.

No description available.

The superoxide radical is considered to play important roles in physiological processes as well as in the genesis of diverse cytotoxic conditions such as cancer, various cardiovascular disorders and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). The detection and quantification of superoxide within cells is of critical importance to understand biological roles of superoxide and to develop preventive strategies against free radical-mediated diseases. Cyclic nitrone spin traps such as DMPO, EMPO, DEPMPO, BMPO and their derivatives have been widely used in conjunction with ESR spectroscopy to detect cellular superoxide with some success. However, the formation of unstable superoxide adducts from the reaction of cyclic nitrones with superoxide is a stumbling block in detecting superoxide by using electron spin resonance (ESR). A chemiluminescent probe, lucigenin, and fluorogenic probes, hydroethidium and MitoSox, are the other frequently used methods in detecting superoxide. However, luceginen undergoes redox-cycling producing superoxide by itself, and hydroethidium and MitoSox react with other oxidants apart from superoxide forming red fluorescent products contributing to artefacts in these assays. Hence, both methods were deemed to be inappropriate for superoxide detection. In this study, an effective approach, a selective mechanism-based colorimetric detection of superoxide anion has been developed by using silylated azulenyl nitrones spin traps. Since a nitrone moiety and an adjacent silyl group react readily with radicals and oxygen anions respectively, such nitrones can trap superoxide efficiently because superoxide is both a radical and an oxygen anion. Moreover, the synthesized nitrone is designed to be triggered solely by superoxide and not by other commonly observed oxygen radicals such as hydroxyl radical, alkoxyl radicals and peroxyl radical. In vitro studies have shown that these synthesized silylated azylenyl nitrones and the mitochondrial-targeted guanylhydrazone analog can trap superoxide efficiently yielding UV-vis identifiable and even potentially fluorescence-detectable orange products. Therefore, the chromotropic detection of superoxide using these nitrones can be a promising method in contrast to other available methods.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

La Prodigiosine est un métabolite secondaire de couleur rouge produit principalement par la bactérie Serratia marcescens. Cette molécule, de structure tripyrrolique, présente des activités antitumorales, immunosuppressives, antibiotiques, antifongiques et antipaludiques. Ses nombreuses activités en font un composé potentiellement intéressant pour des applications thérapeutiques. Notre équipe a développé une méthodologie de synthèse basée sur la réactivité de dérivés pyrroliques vis-à-vis des nitrones et des N-hydroxylamines pour mener sélectivement à des structures dipyrrométhanes et dipyrrométhènes. Cette méthodologie a été le point de départ de la première étude de ce manuscrit. Nous avons ainsi développé une voie d'accès vers la synthèse d'analogues de la Prodigiosine. Ces derniers, substitués en position méso, n'ont jamais fais l'objet d'étude. Pour cela, il a fallu développer une voie d'accès au 4-méthoxy-2,2'-bipyrrole, précurseur principal de la Prodigiosine. Nous avons également mis au point une voie d'accès à des 2,2'-bipyrroles dissymétriques. Ces derniers sont des briques élémentaires utilisés en chimie des porphyrines étendues. Ces macrocycles pyrroliques trouvent des applications dans de nombreux domaines allant des polymères conducteurs aux cristaux liquides en passant par des applications biologiques. Notre méthodologie permet la formation de bipyrroles en six étapes, à partir de substrats facilement accessibles, avec des rendements globaux pouvant atteindre 20 %. Cette méthode a également été étendue à la synthèse du motif terpyrrole. / Prodigiosin is a secondary metabolite mainly produced by Serratia marcescens. This red pigment possessing a tripyrrolic structure, shows antitumor, immunosuppressive, antibiotic, antifungal and anti-malarial activities. These activities make it a valuable compound for therapeutic applications. Our team has developed a synthetic methodology based on the addition of pyrroles onto nitrones and N-hydroxylamines to afford selectively either dipyrromethanes or dipyrromethenes. This methodology has been the starting point of the first study in this manuscript. We have developed a pathway for the synthesis of Prodigiosin's analogues. These analogues, substituted in meso position, have never been studied. In the first stage, it was necessary to develop a synthetic sequence leading to the 4-methoxy-2, 2'-bipyrrole, a precursor of Prodigiosin. We also developed a sequence allowing access to unsymmetrical 2,2'-bipyrroles. These building blocks are used in the chemistry of expanded porphyrins. These pyrrole macrocycles show applications in many fields like conductive polymers, liquid crystals and other biological applications. Our methodology allows the formation of bipyrroles in six steps from readily available substrates with overall yields of up to 20%. This method has also been extended to the synthesis of terpyrrole.

Steroids are one of the essential classes of bioactive compounds and are involved in many biological functions which include their role as signaling compounds, the alteration of membrane fluidity and the regulation of a variety of metabolic processes. In order to identify novel compounds with beneficial pharmacological action, the synthesis of modified steroids is gaining much attention in recent years. Among those analogs, azasteroids are one of the most important classes which display a variety of biological activities, often free from undesirable side effects. The challenges in the synthesis of steroids, particularly azasteroids, and the potential of azasteroids as novel drugs has prompted numerous investigations in this field. The synthetic methods leading to steroidal derivatives (azasteroids) with one or more nitrogen atoms are very limited. Generally, oxidative cleavage of the steroidal rings is needed to introduce nitrogen atom(s) in order to synthesize azasteroids. In the first part of this dissertation, explorations into the synthetic methods needed for making a new steroidal A-ring or seco A-ring on a tricyclic benz[e]indenedione (a dimer compound obtained in connection with continued work on the study of anhydrobases of the isoxazole series) were pursued. In this process, a series of three tricyclic hydrazone compounds have been designed and synthesized to mimic the tetracyclic rigid core structure of azasteroids. We are eager to ascertain if these compounds possesses any interesting biological properties. In continued research on the synthesis of azulenyl and pseudoazulenyl nitrones, (to target ROS generation at the site of mitochondria), the second part of this research was aimed at the synthesis of cationic pseudoazulenyl nitrones with mitochondriotropic properties. Several pseudoazulenyl nitrone derivatives were synthesized using the natural compound valtrate, obtained from the roots of Centranthus ruber. Unfortunately, the attempts made to convert these compounds into the corresponding cationic pseudoazulenyl nitrones failed. However, an interesting pseudoazulenyl dinitrone molecule bearing an imidazole group was prepared. Also, a pseudoazulenyl mono nitrone compound with an electron donating group was synthesized by leaving a highly reactive aldehyde functionality intact for further use in synthetic study.

Over the past decade, bioorthogonal chemistry has emerged as powerful tools used for tracking biomolecules within living systems. Despite the vast number of organic transformations in the literature, only select few reactions meet the stringent requirements of bioorthogonality. There is increasing demands to develop biocompatible reactions that display high specificity and exquisitely fast kinetics under physiological conditions. With the goal of increasing reaction rates as a means for reducing the concentrations of labelling reagents used for bioconjugation, we have developed metal-catalyzed and metal-free alkyne-nitrone cycloadditions as alternatives to azide-alkyne cycloadditions and demonstrate their applications for imaging cell surface proteins. The copper(I)-catalyzed alkyne-nitrone cycloaddition, also known as the Kinugasa reaction, is typically conducted with a Cu(I) catalyst in the absence of air. We have developed highly efficient micelle promoted multicomponent Kinugasa reactions in aqueous media to make the reaction faster and more efficient. Despite good product yields, the slow kinetics, limited substrate scope and competing side-reaction pathways precludes its practical applicability for biological labelling. We have designed and synthesized β-lactam alkyne probes obtained from these reactions for activity-based protein profiling of the activities of membrane proteins. Additionally, we report that alkyne tethered β-lactams serve as surface enhanced Raman spectroscopy (SERS) reporters bound to silver nanoparticles, and demonstrated that alkyne bound silver nanoparticles can be used for SERS imaging cell surface proteins. The strain-promoted alkyne-nitrone cycloaddition (SPANC) was also explored as a rapid alternative bioorthogonal reaction. We found that the reaction proceeded in high yield within aqueous media, and displayed rate enhancements that were 1-2 orders of magnitude faster than analogous reactions involving azides. The scope and kinetics of SPANC was evaluated in model reactions of various nitrones (acyclic and cyclic) with cyclooctynes, with the purpose of identifying stable nitrones that displayed intrinsically faster kinetics than azides in strain-promoted cycloadditions with cyclooctynes. Cyclic nitrones displayed good stability and exceptionally fast reactivity in these reactions. The SPANC reaction exhibited high selectivity in the presence of biological nucleophilic amino acid side chains and the presence of biological media did not adversely affect the reaction. We have utilized SPANC for highly specific labelling of proteins in vitro and for imaging ligand-receptor interactions on the surfaces of live cancer cells. The high selectivity, fast reaction rate, and aqueous compatibility of SPANC makes the reaction suitable for a variety of in vivo biological imaging applications.