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La réaction de SN2’, initialement mise en évidence en 1960 par Crabbé, correspond à l’addition d’un dérivé organométallique du cuivre, préformé ou généré in situ de façon catalytique, sur un substrat possédant un groupe partant en position allylique s’effectuant avec migration de la double liaison, le tout avec en général d’excellents niveaux de régio-, chimio- et stéréo- sélectivités. Au départ de substrats chiraux, cette réaction est en outre stéréospécifique et représente une des meilleures méthodes pour la mise en place de centres stéréogènes carbonés, ce qui est encore, à l’heure actuelle, loin d’être trivial. Au cours de cette thèse, nous avons étudié plus en profondeur cette réaction et l'avons appliquée à divers substrats., Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Since everything we know and around us is made of atoms and molecules, organic chemistry is intimately part of our daily life. Among all the different areas of study of organic chemistry, catalysis is an extremely important area of chemistry for the development of new catalytic systems and new reactions. Utilizing transition metals as catalysts for novel reactions led to a fundamentally significant advancement in organic synthesis by enabling the discovery of previously unheard of reactions and, most importantly, new methods for forming chemical bonds between atoms. Because metal-catalyzed reactions have fundamentally changed the logic by which disconnections are made and organic molecules are synthesized, they are widely used in both industry and academia. Recently, copper-catalyzed cross-coupling reactions have been extended to carbonylative ones. In this context, the research work carried out during the course of this thesis is devoted to the development of new copper-catalyzed carbonylative cross-coupling reactions for the preparation of carbonyl derivatives. In addition, still remaining in the domain of copper catalysis, a second independent subject dedicated to the development of a new synthetic strategy for the preparation of trifluoromethylated alkenes based on a broadly applicable copper-catalyzed trifluoromethylation of vinylsiloxanes was studied in our laboratory. Therefore, this manuscript will be, quite naturally, divided into two distinct parts which will focus on the development of new copper-catalyzed carbonylative cross-coupling reactions (part 1) and the development of a new copper-catalyzed cross-coupling for the trifluoromethylation of vinylsiloxanes (part 2). These two subjects will be discussed in detail in the four chapters of this manuscript. The first chapter will consist of a bibliographical study which will aim to place the first part of this work in its context and which will be devoted to a literature overview of copper-catalyzed carbony, Doctorat en Sciences, info:eu-repo/semantics/nonPublished

An efficient and unprecedented cross-coupling between acylzirconocenes, readily available starting materials conveniently prepared by hydrozirconation of alkenes and a subsequent carbonylation with carbon monoxide, and diaryliodonium tetrafluoroborates is reported. This procedure enables the synthesis of a broad variety of alkyl-aryl-ketones upon simple catalysis with copper cyanide without the need of additional ligands and only requires a low pressure of carbon monoxide generated in situ, in a two-chamber reactor, from N-formylsaccharin., SCOPUS: ar.j, info:eu-repo/semantics/published

Photoredox catalysis combines the energy of light with a photocatalyst able to absorb it and promote electron transfers toward a substrate. In the last two decades, it has been increasingly used in the field of synthetic chemistry, where it allows the generation of highly reactive radical species under mild reaction conditions but has found limited industrial applications due to the needs for expensive noble metal photocatalysts to conduct these reactions.Photoactive copper(I) complexes have been increasingly studied since the discovery of their photochemical properties in 1977, not only because of the attractive availability of copper but also thanks to their innate properties, which upon careful ligand design allow them to compete with photoactive noble metal complexes, notably in the development of OLEDs and for molecular sensing.Therefore, it was not long before scientists started exploiting the interesting photophysical properties and the availability of copper(I) complexes in photoredox catalysis of organic transformations, and in the last ten years, an exponentially-growing number of reports have been published in this regard. These reports demonstrated that copper complexes were efficient to induce a broad range of transformations, but mostly relied on state-of-the-art copper complexes developed for their use in other applications.In this framework, this thesis intends to explore the structure-properties and structure-activity relationships in a class of copper complexes that has been particularly fruitful in photoredox catalysis of organic transformations, and to use the information gathered to design new complexes optimized for their use as photoredox catalysts.To this end, a family of these complexes, designed to exhibit an increased absorption of visible light compared to state-of-the-art complexes of this class, has been developed and their properties have been extensively studied. Their activity on a prototypical photoredox-catalyzed process was also i, Option Chimie du Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Tumors reprogram metabolic pathways to support the bioenergetic, biosynthetic, and redox needs of malignant cells. There is an increasing recognition that the tumor microenvironment drives many of these alterations in the metabolic phenotype of tumor cells, thereby paving the way for the development of specific anticancer metabolism-targeting compounds. In this thesis, we designed and synthesized such inhibitors, including some in the form of prodrugs to be activated in response to the acidic or hypoxic tumor microenvironment. In the first chapter, we designed and synthesized carboxyamidotriazole analogues to inhibit mitochondrial complex I of the oxidative phosphorylation (OXPHOS) pathway. In vitro cellular studies were conducted to evaluate their pharmacological activities, and preliminary structure-activity relationship analysis was obtained. Promising complex I inhibitors were further validated in 3D tumor spheroids. In the second chapter, we designed a pH-sensitive drug delivery system by conjugating a pH-dependent peptide with lipid metabolism-targeting drugs including Etomoxir (CPT1 inhibitor) and T863 (DGAT1 inhibitor), targeting mitochondrial fatty acylCoA uptake and the last step of triglyceride synthesis, respectively. Efficacy was evaluated using liposome models and in vitro cellular assays. In the third chapter, we designed and synthesized hypoxia-activated prodrugs (HAPs). Among the drugs that were modified to be specifically activated under low pO2 upon reduction of a nitro moiety (Part A), we considered COX inhibitor diclofenac repurposed recently as an inhibitor of lactate transport through MCT4 and a traditional antitumor drug tetrandrine. In Part B, a novel HAP model containing a triazene group was designed and synthesized. Mechanisms of triazene probe release by chemical reduction were studied to further gain insights on the potential use of these HAP in tumors. Altogether, the data obtained in this thesis support the feasibility of targeting pec, (SC - Sciences) -- UCL, 2022

Since many years, chemists leveraged the photophysical properties inherent to ruthenium or iridium-based photosensitizers to develop strategies towards conversion of sunlight into chemical energy such as molecular hydrogen or complex organic molecules. However, the scarcity and toxicity of these elements prevent the potential scalability of this kind of system. This is why the development of efficient photocatalytic complexes using cheap and abundant first row metals would offer an important solution to this problem. Due to its abundance in the earth’s crush, the iron element seems perfect to supplant its ruthenium analogue. Nonetheless, the Fe(II)-based polypyridyl photosensitizers suffer from their intrinsic photophysical properties that deactivate non-radiatively the low-lying excited-state and hence reduce its lifetime. Important insights were recently brought by Wärnmark et al. in the conception of Fe(II) and Fe(III)-based photosensitizers through ligand modifications strategy. During this Ph.D. thesis, we have designed and synthesized novel iron-based photosensitizers. Through coordination sphere modifications, we attempted to tune their photophysical properties and then utilized them as potent photosensitizer in photoredox catalysis. By careful investigations, we were able to determine the key parameters that could potential govern a photoreaction and to propose an in-depth reaction mechanism through time-resolved ultrafast spectroscopic techniques., (SC - Sciences) -- UCL, 2022

Targeting enzymes involved in tumor metabolism is a promising way to tackle cancer progression. The inhibition of carnitine palmitoyltransferase 1 (CPT1) by etomoxir (Eto) efficiently slows down the growth of various cancers. Unfortunately, the clinical use of this drug was abandoned because of hepatotoxic effects. We report the development of pH-sensitive peptide (pHLIP)-drug conjugate to deliver Eto selectively to cancer cells exposed to acidic microenvironmental conditions. A newly designed sequence for the pHLIP peptide, named pHLIPd, was compared with a previously published reference pHLIP peptide, named pHLIPr. We showed that the conjugate between pHLIPd and Eto has a better pH-dependent insertion and structuration than the pHLIPr-based conjugate inside POPC vesicles. We observed antiproliferative effects when applied on acid-adapted cancer cells, reaching a larger inhibitory activity than Eto alone. In conclusion, this study brings the first evidence that pHLIP-based conjugates with a CPT1 inhibitor has the potential to specifically target the tumor acidic compartment and exert anticancer effects while sparing healthy tissues.

Cancer cells may stimulate glycolytic flux when O2 becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes. A primary assay measuring L-lactate release as a compensatory mechanism upon OXPHOS inhibition led us to identify 15 hits among 28 derivatives. A secondary assay measuring O2 consumption in permeabilized cancer cells confirmed that 12 compounds among the hits exhibited reversible complex I inhibitory activity. Anticancer effects of a short list of 5 compounds identified to induce more L-lactate release than reference compound were then evaluated on cancer cells and tumor-mimicking 3D spheroids. Human and mouse cancer cell monolayers exhibiting high level of respiration in basal conditions were up to 3-fold more sensitive than less oxidative cancer cells. 3D tumor spheroids further revealed potency differences between selected compounds in terms of cytotoxicity but also radiosensitizing activity resulting from local reoxygenation. In conclusion, this study documents the feasibility to efficiently screen in 96-well plate format for mitochondrial complex I inhibitors based on the capacity of drug candidates to induce L-lactate release.