UY Cergy Paris University
Thursday, December 8, 2022 – 13:00
Organic Chemistry & Interfaces team
Abstract
Nowadays, a whole arsenal of drugs based on peptides and peptidomimetics is available.[1] Their efficacy depends on several factors such as their conformation, hydrophobicity, or resistance to degradation by peptidases. These physicochemical and biological factors can be tuned by the introduction of fluoroalkylated groups within the peptides.[2]
Due to its nature, the peptide bond undergoes a spontaneous cis−trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. The Xaa-Pro peptide bond is subject to cis-trans isomerization characterized by an increased cis population and an activation energy that is low when compared to the other amino acids. Besides, the five-membered ring of the Pro residue can adopt two main distinct conformations (Cg endo- or Cg exo-puckered). Therefore, a variety of proline analogs have been designed in order to control the conformation of the peptide backbone and consequently to modulate the biological activity of peptides.
Our group is interested in the synthesis of enantiopure fluorinated amino acids and their incorporation into peptides. Because of the crucial role of the proline, we have developed efficient synthetic routes for the synthesis of various fluorinated analogues of proline.[3] Here, I will present the main results obtained from NMR and theoretical studies based on model peptides which established the stereoelectronic effects imparted by the CF3 and CF2H groups along the pryrrolidine ring. I will also detail the methodological study developed to optimize their incorporation into peptides. Finally, I will present some applications to peptides of interest.
References
[1] a) M. Muttenthaler et al. Nat. Rev. Drug Discov. 2021, 20, 309; b) L. Wang et al. Signal Transduct. Target. Ther. 2022, 7, 48.
[2] H. Mei, H. et al. Eur. J. Med. Chem. 2020, 186, 111826.
[3] a) G. Chaume et al. Org. Lett. 2006, 8, 6123; b) G. Chaume et al. J. Fluorine Chem. 2008, 129, 1104; c) C. Caupène et al. Org. Lett. 2009, 11, 209; d) G. Chaume et al. J. Org. Chem. 2010, 75, 4135; e) H. Lubin et al. J. Org. Chem. 2015, 80, 2700; f) J. Simon et al. J. Org. Chem. 2016, 81, 5381; g) C. Gadais et al. ChemBioChem 2019, 20, 2513 ; h) N. Malequin et al. Chem. Commun. 2019, 55, 12487; i) S. A. Sanchez et al. Org. Lett. 2021, 23, 382.
Contact
Charlène Gadais : charlene [dot] gadais
univ-rennes1 [dot] fr
