Safety of goods and civilians towards the terrorist risk constitutes a research orientation of public interest, confirmed by the 2013 edition of the “Livre blanc de la Défense et de la Sécurité Nationale”. In particular, the risk of Nuclear or Radiological attack remains one probable and serious risk, following the emergence of nations sufficiently developed and favorable to develop this kind of armament. In this context, it is important to have passive detection of ionizing rays. In our case, we take interest in the detection of neutrons, immutable signature of the presence of materials allowing the preparation of nuclear weapons. In addition to the societal aspect, the economic aspect is crucial because such detectors, containing 3He gas, currently exist, but their lack prevents their deployment on large surfaces. We thus wish to develop polymeric materials allowing the detection of these neutrons at lower costs, as well as a prototype containing these sensors.

Chemical industry must perform a deep mutation in order to create innovative, more environmentally friendly technologies. In this context, olefin metathesis appears as an organometallic reaction having a tremendous potential, and is increasingly used in industrial processes because it shortens production pathways to complex molecules and consequently reduces both production costs and the environmental impact. The aim of this research project is to develop an economically profitable process for the transformation of vegetable oils in valuable chemicals using olefin metathesis and a novel library of tunable Ru-based supported catalysts. The self-metathesis of methyl oleate will be the targeted reaction. In order to lower metal leaching, a major drawback in olefins metathesis, two routes will be explored, depending on the interactions between the ruthenium and the support: 1) use of traditional fixed bed reactors with innovative immobilized catalysts or 2) use of catalysts designed for reversible interactions with solid supports in an innovative reverse flow process. The first route implies drastic efforts to improve catalysts life-time and recycling. Three strategies will be considered for the immobilization: 1) Ionic interactions between an ionic liquid and ionic-tagged catalysts, and impregnation on very promising bio-supports obtained from chitosan or alginates; 2) Reversible interactions between the catalyst and either an amorphous or a mesopored functionalized silica, thanks to Charge Transfer Complexes (CTC) Tags or carbon nanotubes, via p-p interactions. 3) Covalent immobilization of the Ru-complex on a mesostructured functionalized silica leading to isolated and permanently supported Ru-active single sites on silica. These materials must exhibit an optimal compromise between catalytic activity and stability of the metallic species. A key point will be the catalyst robustness, which will ensure no degradation with long-term production time in continuous flow applications and no leaching, thus no toxic metallic residues release in the product. The catalytic material must be obtained both in large quantities and costless for industrial applications. The second route concerns the use of those catalysts that are prone to metal leaching because of weak interactions with the support thus not eligible for the first route. For such cases, the use of a reverse-flow adsorption reactor (RFAR) is proposed. RFAR displays adsorption/desorption sections surrounding a reaction section. The supported catalysts will be used as active species reservoirs, liberating the unsaturated Ru-complex upon olefins feeding. The reactor section will be strictly homogeneous, since the functionalized support by labile ligands will remain in the adsorption section, ready to readsorb the catalyst. The design and use of such dynamic reactors imply researches on adsorption/desorption equilibria, kinetics and reactor simulation and modelling. The final objective is the set up of two industrial processes for the transformation of vegetable oils in valuable chemicals. These processes must be cost effective while being environmentally friendly. The partnership of the project involves five complementary academic teams (ENSCR, Université de Paris Sud (UPS-XI), ENSICAEN, CPE-LCOMS and CPE-LGPC at Lyon), one end-user industrial chemical company (NOVANCE-OLEON), French Institute specialists in oils, fats and derivative products (ITERG) and a start-up (OMEGA CAT SYSTEM) whose business activity is focused on the promotion of technologies associated with olefin metathesis. Being successful, the project will deliver both breakthrough technologies and fundamental knowledge in the fields of olefin metathesis, catalyst-support interactions and reactor design for homogeneously catalysed reactions.

The goal of this project consists in developing new plastic scintillators whose properties of scintillation exceed those of the organic scintillators currently commercially available. The use of fluorescent molecules of organometallic type represents the technological asset to achieve this goal. The improvement of the properties of scintillation will allow increasing the capacities of the scintillators, in the counting and spectrometry necessary for the applications of monitoring of the critical infrastructures, such as for example gamma radiation portal monitors or discrimination between fast neutrons and gamma allowing the detection of radiological precursors of weapons.

Nucleic acid-based therapeutics have emerged and represent today, key targets in a wide range of diseases. Since natural oligonucleotides (ONs) are rapidly metabolized in biological media by nucleases and suffer from a poor cellular uptake, several chemical modifications were envisaged and led to the conception of ON analogs with good biological activities. However, in spite of the large number of ONs that are currently under clinical trials, the FDA approved only few of them. Thus, new series still deserve to be discovered regarding the high potential of ON-based therapeutics and the growing economical market of this field. Our project deals with the design and synthesis of new ON series that would be able to counteract the main limitations of current therapeutic ONs. In front of the importance of the fluorine atom in medicinal chemistry, we will be particularly interested in the preparation of fluorinated nucleic acids that have been less explored nowadays. Indeed, several organofluorinated groups will be introduced onto the 2’-position of nucleosides to increase both the thermal stability of RNA duplex, resistance towards nucleases as well as cellular uptake. To access to these target molecules, automated solid-phase phosphoramidite-based ON synthesis will be privileged. Indeed, new synthetic methodologies based on ionic and radical approaches will be first developed to synthesize the different fluorinated phosphoramidites in each nucleobase series (A, C, G, U). These laters will be then incorporated in various model sequences (siRNA, miRNA) to study their physico-chemical and biological properties.

The objective of this project is to evaluate new "click" reactions adaptable to kinetic target guided synthesis (TGS), such as described by K. B. Sharpless et al. ten years ago. In situ click chemistry has indeed proven to be a new and elegant paradigm for drug discovery. Based on our successful experience on the use of Huisgen cycloaddition on human acetycholinesterase (AChE), which allowed us to estimate scopes and limitations of this reaction, four new reactions will be targeted, namely the “Aubé”, “Pictet-Spengler” and “carbonyle-ène” reactions, as well as the “Kondrat' Eva's“ cycloaddition for which we already have obtained encouraging preliminary results. Our ultimate goal is to exploit these reactions to produce molecules that will aid fighting Alzheimer's disease (AD). AD is a neurodegenerative process occurring in the central nervous system (CNS). It is the most common cause of dementia in elderly. It is clinically characterized by a loss of memory and cognition, associated to a deterioration of the basal-forebrain cholinergic-neurons network and a consequent lack of acetylcholine (ACh) around brain cells. While the process leading to the development of AD is complex and multifactorial, and the etiology of AD is not completely known, it is nowadays clear that AD is a multifaceted illness requiring the combination of synergetic treatment strategies. Although several research strategies have been envisaged in the last decades, these molecules only alleviate the symptoms of the illness, and do not cure it. The current view of AD physiopathology is indeed that its onset and progression are the result of a complex network of genetic predispositions, enzymatic activities, receptors expression, protein interactions, alteration of metal concentrations, cell cycle survival disruption, ion homeostasis dysregulation, protein misfolding, etc. The “multifactorial hypothesis” led to the proposal that the multi-target-directed ligands strategy is needed to treat the disease more efficiently. The first objective in this project will, therefore, be to use the classical Huisgen reaction as well as the above-mentioned, newly-developed click reactions, so as to prepare new multi-target directed ligands (MTDLs) that will act simultaneously on the different players in AD pathology and, thereby, allow a more efficient treatment of the disease. The envisaged MTDLs should combine at least two functionalities, among which acetylcholinesterase (AChE) inhibition, an action against Abeta aggregation, anti-oxidative properties, BACE-1 inhibition, GSK-3 beta inhibition or alpha 7 nAChR activation. The second objective of the project is to use the more complex in situ click chemistry approach for the discovery of potent MTDLs. It is using this methodology, also coined kinetic target guided synthesis (TGS), that Sharpless et al. indeed obtained the most potent AChE inhibitors with a femtomolar inhibitory activity. As for our first objective, we will expand the toolkit of click-reactions beyond the classical Huisgen reaction, so as to produce a wider diversity of possible ligands. Additionally, and based on our already-existing know-how, we will expand the in situ click chemistry to another enzyme involved in AD, viz. BACE-1, which is one of the two enzymes involved in the proteolytic release of the amyloid-beta peptide.