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Aminoacides à conformation contrôlée: Nouvelles approches stéréosélectives et application à la conception de librairies de coudes beta – SAAcoude

Submission summary

Cyclic amino acids, and particularly aminocyclopropanecarboxylic (ACC) acids are important synthetic intermediates or target molecules in medicinal chemistry. They are also used in designing constrained peptidomimetics for structure-activity relationship studies. Racemic ACC analogues and nitrogen heterocycles-based amino acids have been prepared by a number of methods. The synthetic approaches to optically active compounds are less frequent and typically require multi-step sequences and/or tedious resolution procedures. The first part of this project (Reims University) deals with the development of new versatile approaches to optically active alpha-, beta-, and gamma-aminoacids cyclopropane (ACCs) as well as various unnatural proline analogues, which can be regarded as chimeric prolinoaminoacids. The second part of the project (Paris, UPMC) concerns i) the analysis of the conformation preference of these amino acids when introduced in model peptides and ii) the design of small-sized librairies of beta-turns, since it is expected but remain to be proved, that such constrained amino acids should stabilize turn structures. The synthetic work would mostly be based on new methodologies, which have been developed in one of our groups (Szymoniak and collaborators). Among them, the titanium-mediated synthesis of primary cyclopropylamines from nitriles and Grignard reagents offers exciting opportunities to prepare ACCs in catalytic and enantioselective fashion. On the other hand, stereoselective accesses to various ACCs would be examined by using nitriles and unsaturated alcohols, based on a ligand exchange procedure. We are planning to apply this new strategy to a wide range of optically active ACCs including bicyclic proline analogues with a cyclopropane ring. The synthetic part of project also deals with the development of versatile new approaches to heterocycles-based amino acids and especially original proline analogues. These diastereoselective reactions will be the extension of our recent zirconium chemistry directed toward the diastereoselective construction of nitrogen heterocycles. They will be applied to the synthesis of diversely substituted proline analogues as well as azetidine- and piperidine-derived original amino acids. Part of recent ongoing work in the UPMC team is now devoted to the modulation of protein-protein interaction, especially those involving a beta-turn structure. The UPMC team had already developed new efficient methodologies for the synthesis of chimeric proline bearing on C3 the various side chains of natural amino acids and also different strategies for the preparation of beta-2-amino acids. We have recently designed highly stable constrained beta-turns with these chimeric prolinoamino acids. In the quest for stabilized beta-turn structures, without loss of the information carried by the side chains of the i+1 and i+2 aminoacids within the turn, constrained aminoacids such as functionalized beta-prolines (with phi fixed and psi, kappa1 constrained) and cyclopropane aminoacids (with kappa1 fixed and phi, psi, khi2 constrained) represent valuable tools, which will be introduced in the i+1 and i+2 positions. The influence on the flexibility and local/global conformations of these constraints, introduced within model sequences, will be studied by NMR, FTIR and molecular dynamic calculations. Concomitantly, these librairies will be screened, in a proteomic approach to fish out by affinity from lysates proteins interacting with these beta-turns. If successful these molecules may inhibit protein-protein interactions in the cell, or on the surface of the cell, and thus modulate a vital pathway for the functions of the cell. We do not want to pretend that these molecules will be of therapeutic uses but at least at the first stage of this program will help i) to validate or explore the function of its target, and ii) by this strategy to unveil new targets.

Project coordinator

Jan SZYMONIAK (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE CENTRE-EST)

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

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE CENTRE-EST
UNIVERSITE PARIS VI [PIERRE ET MARIE CURIE]
UNIVERSITE DU MAINE

Help of the ANR 348,000 euros
Beginning and duration of the scientific project: - 36 Months

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