Synthesis and study of decoordinable units in ferrous chelates for the design of magnetogenic molecular probes

Cette thèse a pour but la synthèse de complexes de Fe(II) ayant la capacité de changer d’état de spin par l’action d’un analyte, afin de les appliquer à l’Imagerie par Résonance Magnétique Moléculaire, défi actuel du domaine. Dans ce but, l’équipe a déjà développé différents systèmes moléculaires permettant ce changement d’état de spin en présence d’une enzyme cible. Cependant, aucun de ces systèmes n’est actuellement utilisable pour des études in vivo, les plus développés étant notamment limités par leur pH d’activation trop faible. C’est donc dans l’objectif d’augmenter ce pH d’activation que ma thèse s’inscrit, en étudiant l’impact de nouvelles unités décoordonnables sur ce pH, mais aussi sur les propriétés magnétiques des complexes ferreux. Dans un premier temps, ces travaux se sont tournés sur l’étude de fonction de type imidate. Pour cela, la méthodologie de synthèse d’une telle fonction chimique a été étudiée permettant de mener à la synthèse de deux sondes répondant à une activité enzymatique. Leur activation enzymatique a pu être suivie par différentes analyses. Une étude du composé modèle pH-répondant a également été menée afin d’apporter une compréhension plus fine du système. Dans un second temps, l’étude de systèmes plus flexibles a été réalisée en incorporant des unités de type amidine, reliées au ligand macrocyclique via un pont éthylène. Pour cela, de nouvelles voies synthétiques ont été mises en place afin de concevoir des complexes stables en milieu aqueux. L’étude de ces nouveaux systèmes a pu mettre en avant l’impact positif du pont éthylène sur le pH d’activation de sondes. Pour finir, une nouvelle unité guanidine substituée a été étudiée. Pour cela, elle a été incorporée à un complexe modèle protonable et à un complexe modèle de sonde initiale après carbonylation de l’unité. Cette guanidine permet de stabiliser le complexe ferreux sur l’ensemble de la gamme de pH. Toutefois, l’état bas spin n’est pas atteignable avec un tel ligand, et ce même après carbonylation de la guanidine.The aim of this thesis project is to synthesize Fe(II) complexes that can change their spin state by the action of an analyte, in order to apply them to Magnetic Resonance Imaging. Toward this objective, our team has already developed different molecular systems allowing this spin state change in the presence of a target enzyme. However, none of these systems is currently applicable for in vivo studies, as the most developed is limited by its low pH of activation. Thus, the objective we are focused on is to increase the activation pH. Our main strategy is to study of the impact of new basic units on both this pH and the magnetic properties of the iron complexes.Firstly, this work focused on imidate type functions. For that, we performed a methodologic study that enable us to synthesize two probes responding to an enzymatic activity. Their enzymatic activation could be followed by different analyses, such as UV-Vis spectroscopy or mass spectrometry. Moreover, the pH-responsive model compound was carried out in order to provide a more detailed understanding of the system.Secondary, several more flexible systems containing amidine type units linked to the macrocyclic ligand via an ethylene bridge were prepared. For this purpose, new synthetic routes were set up in order to design stable complexes in aqueous media. The analysis of these new systems highlights the positive impact of the ethylene bridge on the activation pH of the probes.Finally, a new cyclic substituted guanidine moiety was investigated. It was incorporated into a protonable complex and also into an initial probe’s model complex after carbonylation of the unit. This guanidine aims to stabilize the Fe(II) complex over the entire acidic pH range. However, the low spin state is not achievable with such ligand, even after carbonylation of the guanidine

Early/Late Heterobimetallic Tantalum/Rhodium Species Assembled Through a Novel Bifunctional NHC-OH Ligand

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Synthesis & Evaluation of Novel Mannosylated Neoglycolipids for Liposomal Delivery System Applications

Glycosylated NPs, including liposomes, are known to target various receptors involved in cellular carbohydrate transport, of which the mannoside binding receptors are attracting particular attention for their expression on various immune cells, cancers, and cells involved in maintaining central nervous system (CNS) integrity. As part of our interest in NP drug delivery, mannosylated glycoliposomal delivery systems formed from the self-assembly of amphiphilic neoglycolipids were developed, with a C12-alkyl mannopyranoside (ML-C12) being identified as a lead compoundcapable of entrapping, protecting, and improving the delivery of structurally diverse payloads. However, ML-C12 was not without limitations in both the synthesis of the glycolipids, and the physicochemical properties of the resulting glycoliposomes. Herein, the chemical syntheses of a novel series of mannosylated neoglycolipids are reported with the goal of further improving on the previous ML-C12 glyconanoparticles. The current work aimed to use a self-contingent strategy which overcomes previous synthetic limitations to produce neoglycolipids that have one exposed mannose residue, an aromatic scaffold, and two lipid tails with varied alkyl chains. The azido-ending carbohydrates and the carboxylic acid-ending lipid tails were ligated using a new one-pot modified Staudinger chemistry that differed advantageously to previous syntheses. The formation of stable neoglycoliposomes of controllable and ideal sizes (≈100–400 nm) was confirmed via dynamic light scattering (DLS) experiments and transmission electron microscopy (TEM). Beyond chemical advantages, the present study further aimed to establish potential improvements in the biological activity of the neoglycoliposomes. Concanavalin A (Con A) agglutination studies demonstrated efficient and stable cross-linking abilities dependent on the length of the linkers and lipid tails. The efficacy of the glycoliposomes in improving cytosolic uptake was investigated using Nile Red as probe in immune and cancer cell lines. Preliminary ex vivo safety assessments showed that the mannosylated glycoliposomes are hemocompatible, and non-immunogenic. Finally, using a model peptide therapeutic, the relative entrapment capacity and plasma stability of the optimal glycoliposome delivery system was evaluated and compared to the previous neoglycoliposomes. Overall, the new lead glycoliposome showed improved biological activity over ML-C12, in addition to having several chemical benefits including the lack of stereocenters, a longer linker allowing better sugar availability, and ease of synthesis using novel one-pot modified Staudinger chemistry