CE07 - Chimie moléculaire, Chimie durable et procédés associés

Constrained oligonucleotides-based Catalysts – CoolCat

CoolCat

Constrained oligonucleotides-based Catalysts

Exploitation of the G4 polymorphism for asymmetric catalysis

The objectives of the project consist in the joint use: <br />- of constrained oligonucleotides on a peptide platform in a single topology, <br />- metal complexes, <br />- tetrads of synthetic guanines, <br />for asymmetric catalysis reactions, in particular sulfoxidation.

The constrained G4 structures are synthesized and characterized at DCM, then used in conjunction with metal complexes to test asymmetric catalysis at LCMB. These experiments are done without a priori, indeed, it is, for the moment very difficult to find a rational between nucleic acid structures / metal complex / type of reaction in the literature. We use metal complexes that have already proven themselves for the development of artificial enzymes in association with proteins. We are also exploring the possibility of directing the catalysis reactions with DNAzyes (G4 / heme association) by «covering« the heme with a tetrad of synthetic guanine (ICMUB).

On the Grenoble site (UGA), doctoral student Yoann Colas was recruited. The synthesis of constrained oligonucleotides was undertaken at DCM and that of metal complexes at LCBM. Sulfoxidation conditions (LCBM) have been developed. Indeed, at first Mr Colas carried out the synthesis of constrained G-quadruplexes (RG4) of topology called «parallel«; following the synthesis of copper-bipyridine complexes (Cu.bipy), he then developed the sulfoxidation conditions by reproducing the results obtained by the Can Li team (Chemical Communications 2016, 52, 9644). As expected, the parallel Cu.bipy / RG4 system does have a catalytic activity, however it does not induce asymmetry. These results demonstrate that the RG4 platform has the same properties as the natural system. The antiparallel RG4 system, which will allow asymmetric catalytic reactions to be carried out, has been prepared but the confinement did not allow us to test its effectiveness, this will be done as soon as the PRAs of DCM and LCBM allow it. In parallel with these investigations, work to obtain chiral synthetic guanine (TASQ) tetrads was undertaken at the Dijon site (ICMUB). A post-doctoral fellow has been recruited, Ms. Pauline Lejault. The specifications of these syntheses, adopted in kick-off meeting, include 2 essential elements: the modification of the central template of the TASQ to allow covalent grafting on the RG4 on the one hand, then the insertion of chiral arms around the tetrad of guanines, on the other hand. Of these 2 spots, the first is by far the most difficult. The ICMUB has invested the energy necessary to obtain a TASQ template that can be combined using bioorthogonal chemistry (called click chemistry).

The initial technical difficulties delayed the valuation of the project deliverables. In particular, the breakdown of the DCM's circular dichroism delayed the characterizations of RG4 and therefore all of the tasks that depended on it. Now that the conditions for the study of sulfoxidation are ready, it is likely that the first valuable results will not be long in coming.

European patent application No. 20315084.2, filed March 31, 2020

Poster METBIO summer School 2019 « Constrained Oligonucleotide based catalyst » 6-11 octobre 2019 – Yoann Colas

In this project, we propose to develop novel and eco-friendly catalysts for stereoselective transformations based on G-quadruplex (G4) nucleic acids constrained in a single controlled topology (RG4) and metal complexes. G4s have already been used for many catalytic processes when metal complexes are used as cofactors (reactions referred to as ‘DNAzyme’ reactions). It has been demonstrated that the G4 topology, known to be quite diverse, has a great influence on the obtained enantiomeric excess; however, these different topologies are in constant equilibrium (interconvertion) in the conditions of the experiments (nature of the buffer, cation content, pH, etc.), making the rationalization of the G4 efficiency as pre-catalysts rather difficult, in terms of both efficiency per se and opportunities to improve the process (recyclability, enatioselectivity, etc.). Moreover, the use of native G4s precludes experimental conditions that require harsher conditions (temperature, organic co-solvants, etc.), therefore decreasing the scope and interest of DNAzyme-type catalytic transformations.
One of the main goals of the CoolCat project is to chemically constrain G4s into a single topology (RG4) to improve both their chemical stability and their catalytic competences, and use them with efficient metallic cofactors to design innovative catalytic cocktails with expanded application scopes. :
1-First, the synthetic metals-complexes, known and used for developing artificial metalloenzymes, will be used with RG4 pre-catalysts; to date, only a few metal complexes (mostly copper(II) based) has been used for DNAzyme-type reactions and we anticipate that using new metal complexes will improve both the efficiency and scope of the process;
2-Second, we will develop brand new enantioselective DNAzyme-type reactions, thanks to the addition of chiral cofactors, here TASQ (for template-assembled synthetic G-quartets). TASQ have indeed been demonstrated to be valuable DNAzyme boosting agents, sandwiching the cofactor (i.e., heme) in between G4 and TASQ, therefore creating a binding pocket optimized for catalysis; using chiral TASQ will thus afford the possibility of catalysing chiral reactions, of utmost interest for industry-driven applications.
We thus believe that this project will pave the way towards new, sustainable, efficient and versatile catalysts.

Project coordinator

Monsieur Nicolas SPINELLI (DEPARTEMENT DE CHIMIE MOLECULAIRE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LCBM LABORATOIRE DE CHIMIE ET BIOLOGIE DES MÉTAUX
ICMUB INSTITUT DE CHIMIE MOLECULAIRE DE L'UNIVERSITE DE BOURGOGNE
DCM DEPARTEMENT DE CHIMIE MOLECULAIRE

Help of the ANR 439,947 euros
Beginning and duration of the scientific project: December 2018 - 36 Months

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