The chemistry of the interstellar medium (ISM) has become an important area of research in recent years. Thanks to instrumental developments, many new molecules are discovered every year, increasing our knowledge of the complexity of the ISM. The physical conditions in such regions – characterized by very low temperature and density - are very different to what we experience on Earth. It has been necessary for experimental chemists to develop novel techniques to measure the reactivity of chemical species in ISM-like conditions. It is only recently however that astrochemists have begun to understand the importance of neutral-neutral reactions in the ISM, whose behaviour at low temperature remained largely unknown until recently. Nevertheless, astrochemical reaction networks include studied and unstudied neutral-neutral reactions alike, with the rate coefficients for the unstudied reactions being simply estimated in the model. Thus, the chemistry in these models, which is largely driven by not quantified reactions, is subsequently used by astronomers to simulate the chemistry of the ISM in star and planet forming regions. To draw any substantial conclusions from the comparison between the observations and the models, it is crucial to know the model limitations due to uncertainties in the reaction rate coefficients. In this proposal, we wish to bring together different but complementary fields: experimental chemists studying low temperature reactions and astronomers modelling interstellar chemistry. The astronomer of our project is working actively to improve chemical networks for the ISM. She has developed a number of numerical tools to estimate the uncertainties in theoretical species abundances due to rate coefficient imprecision to give a quantitative meaning to the model predictions. She has also developed methods to prioritize reactions that need to be studied by experimental chemists. The chemists of our project have been working for several years on the kinetics of neutral-neutral reactions at low temperature. This team is currently working on the creation of a unique and comprehensive chemical database for astrochemistry (the ISM and planetary atmospheres): KIDA (KInetic Database for Astrochemistry). Such a tool is required to optimize the efficiency of the collaboration between chemists and astrochemists. KIDA is constructed to be useful for astrophysicists and planetary scientists, and to make the chemists work visible to the entire community. This ANR proposal concerns the development of KIDA and the improvement of the data for nitrogen chemistry contained within. For the construction of KIDA, we ask for an assistant engineer who will be responsible for the development of the web interface and for feeding the database. The second part of this proposal concerns the construction of a new experiment to measure the reactivity of atoms with radicals. Although these processes present a challenge for experimentalists, they would be a significant advance for astrochemistry since such reactions are highly important in the ISM. With this new experiment, we would also be able to measure absolute branching ratios for the products of these reactions. Although N-bearing chemistry is typically used to probe the chemical processes that occur during the cold pre-stellar phases, reactions between N atoms and radicals have never been studied at low temperature. We will focus on the most important reactions of atomic nitrogen, identified by the numerical tools previously described. In order to utilize all the information obtained by the experimentalists, we will improve the numerical tools developed to simulate the interstellar chemistry and in particular the treatment of branching ratios uncertainties. Using the new experimental results and new astrochemical models, we will make a detailed analysis of the impact of the measured rate coefficients on the chemistry in star forming regions. Considering the sensitivity of present models to the selected reactions, we expect significant changes in the predictions for nitrogen chemistry in the ISM. The final goal of the project is to improve the predictions of chemical models for the different stages of star and planet formation and be ready for the most powerful observing instruments in this field: the Herschel Space Observatory (HSO) and the Atacama Large Millimeter Array (ALMA).

The recent development of genomics and proteomics has allowed the identification of protein-protein interactions and protein-nucleic acid interactions as major classes of therapeutic targets. Among the 22,000 different human proteins, it is estimated that 80% are involved in complexes of two or more proteins. However, protein surfaces involved in interactions with other proteins or with nucleic acids rarely possess well defined grooves or active sites to bind to a small molecule. Standard pharmaceutical strategies making use of small molecule inhibitors are thus poorly adapted to inhibit protein-protein interactions, and new strategies to target protein surfaces are needed. Indeed, medium sized and large molecules are increasingly being considered as therapeutic agents. The potential of large peptides, oligonucleotides and proteins (especially antibodies) is being intensely investigated. In each of theses classes of molecules, examples exist that have made their way to the market for therapeutic use - over 18 antibodies have already been approved. In this context, foldamers, or synthetic oligomers having well defined conformations resembling those of peptides and nucleotides, have emerged as a very promising class of medium sized molecules. Some foldamers have already been shown to recognize a protein surface and to potentially alter its biological function. This project is based on a new foldamer design recently discovered by one of the participants. The project proposes to improve this design in order to produce and characterize synthetic foldamers capable of inhibiting specific DNA-protein interactions. Such interaction are indeed of immediate relevance in cancer therapy as a large number of DNA-binding proteins are essential to many DNA transactions such as transcription, replication and/or DNA recombination, transactions on which tumor cell growth relies. The project thus aims at significantly advancing the state-of-the-art in foldamer design, in the strategies to recognize protein surfaces, and in approaches to inhibit DNA-binding proteins. Several groups with a long standing experience of bilateral collaborations have been assembled together in this project so as to bring a very wide array of competences in biorganic, supramolecular and synthetic chemistry, in molecular modeling, in structural studies by NMR and x-ray crystallography, in analytical biochemistry, in proteomics, and in molecular pharmacology, all working in different departments of the Bordeaux University campus. Because of potential patenting opportunities offered by this project, the abstract above, which is meant to become public as per ANR rules, has purposely been written so as not to disclose key concepts or structures.

In the EVIDEN project, we are interested in an emerging area in Information Visualization which deals with the exploration and the visual analysis of dynamic data. Our objective is to devise methods and algorithms for the visualization and navigation of dynamic and relational data. Following the visualization "pipeline", research in the EVIDEN project focuses on four main topics: 1/ Definition of a data structure that is versatile, flexible and optimized enough to store large dynamic and relational data. This data structure must be able to guarantee efficient access and update times. 2/ The design of methods for the decomposition and extraction of regions of interest in dynamic data. Decomposition methods must, on one hand, group similar elements and, on the other limit changes during data evolution. Methods to extract regions of interest must allow the detection and the extraction of sub-networks with atypical behaviours. 3/ The design of efficient methods for the visualization of dynamic data: we focus on two main topics, the visual representation of the dynamic data and the visual representation of data evolution. 4/ The design of interaction methods for dynamic data: adapting and/or formally redefining interaction methods for static data as in previous work is required by data evolution and dynamism. The types of problems that the EVIDEN project is addressing emerge naturally in the application domains of bioinformatics and biology. Ultimately, it aims at contributing to the Health sciences. Other application domains could also benefit from these results.

Multicomponent reactions (MCR) have recently garnered a lot of attention, these processes offering an efficient access to a broad range of molecular diversity in a limited number of operations. While MCRs based on ionic and organometallic reactions have enjoyed a wide interest, such is not the case for multicomponent reactions relying on free-radical processes. In this project, we propose two novel free-radical mediated three-component processes that we called carbo-alkenylation and alkynylation. These reactions are based on the coupling between an electrophilic radical species, generated from the corresponding halide or xanthate, an electron-rich olefin and an electron-poor acceptor (unsaturated sulfones and nitroolefins). In the first part of the program, the nature of the different partners will be varied as to determine the best reacting system. In parallel, DFT calculations will be performed to establish a reactivity scale between the different components and to study the mechanism of the addition of nucleophilic radicals onto vinyl- and alkynylsulfones. Experimental and theoretical reactivity scale will be compared as to establish a predictive tool for these free-radical MCRs. A diastereocontrolled version of the carbo-alkenylation and alkynylation above will then be devised using chiral allylsilanes and allylic alcohols that should provide an access to enantioenriched adducts. We also envision, as a long-term objective, developing organocatalyzed enantiocontrolled carbo-alkenylation and alkynylation. Such a process has no precedent in the literature and appears as very challenging. We will thus start our study by devising an enantioselective version of a carbo-oximation reaction that we developed recently. Enantioselective carbo-alkenylation and alkynylation will be studied subsequently based on these preliminary results. For this purpose, activation of the electrophilic radical precursor and/or activation of the acceptor will be investigated using chiral Lewis and Brønsted acids. The last part of the project will finally focus on the development of new domino processes involving two successive multicomponent reactions. Our objective is to perform such post-functionalizations in a single pot, the adduct generated during the first MCR serving as a new component for a second MCR. Three different types of domino processes will be investigated. We will first study a free-radical carbo-alkenylation/1,4-addition/olefination domino process, relying on Julia or Horner-Emmons olefinations. Using acylsilanes as radical precursors, we will also develop an unprecedented cascade where a 1,4-addition of a nucleophile onto a vinylsulfone, followed by a cyclisation onto the acylsilane, will trigger a Brook rearrangement, to eventually provide functionalized silyl enol ethers. Finally, a third domino process will be developed based on an intramolecular Michael-type cyclisation/olefination sequence that should afford new unsaturated cyclic or polycyclic systems. These domino processes will be first tested on model compounds and their value illustrated with straightforward synthesis of small natural products. As a summary, we plan developing new free-radical additions of functionalized carbon fragments across the pi-system of non activated olefins. Such processes result in the neat formation of two new C-C bonds and the generation of a stereogenic center, which stereochemistry should be controlled using organocatalysis. On the whole, this project proposes to tackle fundamental aspects of radical chemistry, including the reactivity of olefins and the enantiocontrol in C-C bond formation under radical conditions.