Institut de Chimie Moléculaire et des Matériaux d'Orsay

Chimie Peptidomimétique Photochimie, Procédés Alternatifs - CP3A

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Peptides

We are interested in developing synthetic tactics for the multi-step construction of cyclic peptide natural products which feature unusual β-aminoacid components. One completed task is the total synthesis of cyclotheonamide C. The cyclotheonamides are a family of macrocyclic pentapeptides isolated from Theonella sponges. They are inhibitors of serine proteases of the trypsin family and have nanomolar IC50 values for thrombin. The first total synthesis of cyclotheonamide C was achieved via three complementary strategies, each involving the construction of the α-keto-β-Arg residue during the peptide coupling step.

S. P. Roche, S. Faure, D. J. Aitken, Angew. Chem. Int. Ed. 2008, 47, 6840-6842; S. P. Roche, S. Faure, L. El Blidi, D. J. Aitken, Eur. J. Org. Chem. 2008, 5067-5078; S. Faure, T. Hjelmgaard, S. P. Roche, D. J. Aitken, Org. Lett. 2009, 11, 1167-1170.

In an ongoing project aimed towards a total synthesis of microsclerodermins C, D and E, a family of cyclic hexapeptides isolated from marine sponges, we established a very short route to the complex α-hydroxy-β-amino acid component using chiral sulfinimine chemistry. This work led us to reconsider the mechanistic aspects leading to the observed diastereoselectivity in the key condensation step. T. Hjelmgaard, S. Faure, P. Lemoine, B. Viossat, D. J. Aitken, Org. Lett. 2008, 10, 841-844.

For our work on peptide-based foldamers, see this page (link).

Other peptide related studies are conducted in a collaborative context: PNA with Prof T. Vilaivan (Bangkok) and actinide-complexing peptides with Prof E. Simoni (Orsay).

Pyrrolidinyl peptide nucleic acid homologues: effect of ring size on hybridization properties. W. Mansawat, C. Vilaivan, A. Balazs, D. J. Aitken, T. Vilaivan, Org. Lett., 2012, 14, 1440-1443. The effect of ring size of four- to six-membered cyclic β-amino acid on the hybridization properties of pyrrolidinyl peptide nucleic acid with an alternating α/β peptide backbone is reported. The cyclobutane derivatives (acbcPNA) show the highest Tm and excellent specificity with cDNA and RNA.

 

Thermodynamic and structural investigation of synthetic actinide–peptide scaffolds. S. S, A. Jeanson, J. Roques, P. L. Solari, F. Charnay-Pouget, C. Den Auwer, D. J. Aitken, E. Simoni, Inorg. Chem., 2016, 55, sous presse (DOI: 10.1021/acs.inorgchem.5b02379) Aspartate-rich pentapeptides with different structural properties were studied to rationalize the structure-affinity relationships. Carbonyl−metal interactions affected the entropy in the case of europium, while the larger uranyl cation was mostly affected by preorganization and steric effects, so that the affinity was enhanced through enthalpy.