title: Molecular building kit of fused-proline-derived peptide mimetics allowing specific adjustment of the dihedral Psi angle.
abstract: Proline-derived peptide mimetics have become an area of paramount importance in peptide and protein chemistry. Since protein crystal structures frequently display Psi angles of 140-170 degrees for prolyl moieties, our intention was to design a completely novel series of 2,3-fused-proline-derived lactams covering this particular conformational space. Extending our recently described toolset of spirocyclic reverse-turn mimetics, we synthesized pyrrolidinyl-fused seven-, eight-, and nine-membered unsaturated lactam model peptides taking advantage of Grubbs' ring-closing metathesis. Investigating the seven-membered lactam 3a by means of IR and NMR spectroscopy and semiempirical molecular dynamics simulations, we could not observe a U-turn conformation; however, increasing the ring size to give eight- and nine-membered congeners revealed moderate and high type IotaIota beta-turn inducing properties. Interestingly, the conformational properties of our model systems depend on both the ring size of the fused dehydro-Freidinger lactam and the position of the endocyclic double bond. Superior reverse-turn inducing properties could be observed for the fused azacyclononenone 3e. According to diagnostic transanular NOEs, a discrete folding principle of the lactam ring strongly deviating from the regioisomeric lactams 3c,f explains the conformational behavior. Hence, we were able to establish a molecular building kit that allows adjustments of a wide range of naturally occurring proline Psi angles and thus can be exploited to probe molecular recognition and functional properties of biological systems.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052, Erlangen, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Einsiedel
authors.forename: Harald
authors.initials: H
authors.lastname: Lanig
authors.forename: Reiner
authors.initials: R
authors.lastname: Waibel
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000138:chemical synthesis*; D007536:Isomerism; D007769:Lactams / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis*; D011392:Proline / Q000031:analogs & derivatives*; D011487:Protein Conformation; D017510:Protein Folding; D011759:Pyrrolidines / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D007769:Lactams; D010455:Peptides; D011759:Pyrrolidines; D011392:Proline