SUMMARY AND ADEQUATION TO THE CALL The present program is a fundamental research project aimed at developing innovative catalytic tools for specifically addressing at short- and mid-term, respectively, two contemporary synthetic industrial challenges: i) the regioselectivity limitations of metal-catalysed direct C–H functionalization of heteroaromatics, and ii) the restrictions in organocatalytic (non-metal) C–O bond activation within CO2 resource. We propose, on the basis of air-stable, temperature-robust versatile ferrocenyl platform (Fc), to design new hybrid acidic (Brønsted and Lewis acids) phosphine ligands with adaptive structures. Additionally, the ferrocene ligand synthesis proposed herein, because of this adaptive aspect, allows also for the synthesis of novel methylamino/borane species that can be valued in further organocatalytic (non-metal) catalysed C–H functionalization of heteroaromatics. Thus, entire new classes of ligands would be designed from a careful structure/reactivity approach (experimental and computational), and would provide auxiliaries for palladium-catalysed C–H functionalization with new selectivity, as well as potentially marketable organocatalysts for CO2 activation and heteroaromatic C–H functionalization – beyond the current proofs of concept. Owing to the robustness and versatility of the targeted tools the potential for industrial application would be much reinforced. This project, in addition to address several fundamental aspects (cooperative ligands in metal and organocatalysis) adequately suits the terms of the call Axe 4: “Chimie Durable, produits, procédés associés” in the “Défi 3 : Stimuler le renouveau industriel”. Several claims in the call perfectly fit the present project, i. e.: “La chimie doit aujourd’hui répondre aux enjeux du développement durable …Pour cela, elle doit accélérer l’évolution de ses pratiques pour réduire sa consommation en matières premières, son coût énergétique et son impact environnemental…la recherche de matières premières alternatives activation du CO2, de molécules C1-C3…”. The applied objective fits the terms of the call concerning “La catalyse est un principe essentiel de la chimie durable et au cœur des grands défis industriels de demain. Les innovations attendues concernent : (i) tous les types de catalyse à savoir … catalyse organométallique, organocatalyse…”. As mentioned above and further detailed below concerning “Adaptive hybrid ligands”, the bifunctional ferrocenes we propose for development (phosphino/carboxylate, phosphino/borane, amino/borane) are the results of a rational conception based on the robustness of the ferrocene platform, intramolecular CMD concept, and Lewis pairs chemistry. Thus, as mentioned in the call this was done for generating innovation “Afin de favoriser l’émergence de ces innovations, une approche basée sur la conception rationnelle (relations structure…) des catalyseurs est à privilégier.” Since the Dijon-Rennes consortium in previous projects successfully designed ligands for promoting difficult C–H functionalization: ligands which are now commercialized and available worldwide, the credibility of this consortium is recognizable. Its extension to international cooperation with a north-american research group of the highest level is also a strong point of this ANR project.

MIPEnz-Decontam is a multidisciplinary project aimed to develop innovative decontamination tools able to detoxify, under mild conditions, a broad spectrum of pesticides and chemical warfare agents involved both as vesicants and organophosphorus nerve agents. By a unique combination of established expertise in synthetic organic, smart polymers, supramolecular and macromolecular chemistry, the design of original Molecularly Imprinted Polymers as enzyme mimics based on a recently proven strategy, will allow to provide, for the first time, efficient broad spectrum solutions against the unresolved issues related to the use and the stockpiling of chemical weapons and pesticides. Based on a strong and complementary know-how, well established expertise, and longstanding fruitful collaborations among the three partners, our challenging approach will culminate on the discovery of novel biomimetic MIP to afford effective technologies, with high socio-economic impact in the civilian and military defence.

Phenoxyimines (FI) and Salen are ubiquitous ligands that are widely used, particularly in organometallic catalysis, with various industrial applications. However, one inherent drawback of their structure is the presence of electrophilic imine(s), which can react and cause a deleterious drop in catalytic performance. MORFAL aims at developing a related class of FI and Salen ligands, where the imine function will be replaced by a trisubstituted amidine giving rise to new phenoxy-amidine ligands (FA). The amidine moiety should provide higher stability and electron-donating ability making FA ligands particularly well suited for stabilising highly reactive cationic or neutral metal species. Considering that the hard character of FA ligands (N,O donor atoms) is best suited for early metals, the coordinating ability of FA ligands will be studied with group 2-4 elements. FA group 4 metal complexes will be targeted for the production of UHMWPE and for the stereoselective polymerisation of propylene. The use of FA ligands more tolerant to alkylating or reducing agent than FI should facilitate the access to well define active cationic species for olefin polymerisation and prevent alkylation and/or reduction of the ligand backbone during the polymerisation reaction. The sigma and ?-donor ability of FA ligands should also contribute to enhance the thermal stability of the active cationic species and thus allow to maintain high catalytic performance when more drastic reaction conditions (temperature, pressure) are required. MORFAL aims also at developing FA-based catalysts for hydrophosphination reaction from early transition metals or even the large alkaline earths Ca-Ba. Special attention will be paid to promote asymmetric catalytic HP using chiral FA early metal complexes. FA ligands are expected to be more suitable than FI for this reaction, which otherwise can undergo intramolecular hydrophosphination.

2in1-ADRC project aims at the development of a new class of therapeutic agents combining advantages of Antibody Drug Conjugates (ADC) and those of Targeted Radiopharmaceuticals (TRP) and compensating for their respective weaknesses, in order to ensure selective delivery of the killing payload at the tumor site while avoiding as much as possible off-target payload release, thus reducing deleterious side effects. A versatile platform will be used for modular conjugation on bispecific biovectors of i) a DOTA chelator for either 177Lu or 225Ac for beta- or alpha therapy respectively, ii) a cytotoxic drug. Proof of concept of the added value of loading a single targeting ligand with two different killing payloads will be achieved through in vitro and in vivo studies of antitumor efficacy of bispecific dual payload bioconjugates, so-called ADRC, in the context of two clinically relevant case studies. We expect that the outcomes of this project will pave the way for the design of a next generation of targeted therapeutic agents, with complementary activities on different cell subtypes and tumor settings, resulting in more potent antitumor efficacy than standard ADC or TRP on aggressive or advanced cancers. This approach will also enable to lower the respective dosing of each individual payload for a better tolerance. Beyond this project, the skills and knowledge developed by the partners will be implemented in a broader R&D program to prepare for transfer to the clinic.

Alternative nucleic acid structures encompass all DNA structures that deviate from the canonical Watson-Crick double helix, or duplex-DNA. These structures are currently being actively studied to understand where, when and how they fold in human cells and to identify the biological processes they are involved in. In light of the most recent results, alternative DNA structures are becoming key players in modern genetics and promising targets for chemotherapeutic interventions. The emblematic example of alternative nucleic acid structures is undoubtedly the DNA quadruple helix, or quadruplex-DNA, whose biology is investigated for more than two decades now. In sharp contrast, the study of DNA junctions, including three-way DNA junctions, or TWJs, is only emerging. Yet, TWJs are known to be involved in severe genetic diseases referred to as REDs (for Repeat Expansion Diseases), such as Huntington diseases or Myotonic dystrophy for instance. In spite of this, no efforts have been yet invested to assess the existence and prevalence of TWJs in our genome, with the notable exception of a study that was very recently published (2021) by the consortium of the present project. Therefore, we propose here to continue this research effort in order to decipher the biological and strategic relevance of TWJs, thanks to the implementation of the most recent and efficient chemical biology tools and techniques. This effort will be resolutely multidisciplinary (combining organic and theoretical chemistry, biochemistry and biophysics, molecular and structural biology, which are embodied by the partners of the project) and translational given that we will make all the molecular tools, protocols and techniques developed in the framework of this project available to all through a suited protection, dissemination and exploitation strategy.