Molecular Building Kit of Fused-Proline-Derived Peptide Mimetics Allowing Specific Adjustment of the Dihedral Ψ Angle

• Published in: Journal of organic chemistry Vol. 72; no. 24; pp. 9102 - 9113
• Main Authors: Einsiedel, Juergen, Lanig, Harald, Waibel, Reiner, Gmeiner, Peter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.11.2007; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Biomimetic Materials - chemical synthesis; Chemistry; Chemistry, Organic; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Isomerism; Lactams - chemical synthesis; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Organic chemistry; Peptides; Peptides - chemical synthesis; Physical Sciences; Preparations and properties; Proline - analogs & derivatives; Protein Conformation; Protein Folding; Pyrrolidines - chemistry; Science & Technology; Spectroscopy, Fourier Transform Infrared; DESIGN; POTENT; NMR; ANALOGS; AMINO-ACIDS; CHIROSPECIFIC SYNTHESIS; LACTAMS; CONFORMATION; METATHESIS; BETA; Nine membered ring; Peptides; Nitrogen heterocycle; Lactam; Metathesis; Molecular dynamics method; Proline; NMR spectrometry; Pyrrolidine derivatives; Unsaturated compound; Eight membered ring; Molecular probe; Semiempirical method; Chemical synthesis; Folding; Ring size; Peptidomimetic compound; Protein; Spiran; Infrared spectrometry; α-Aminoacid; Cyclization; Biomimetic compound; Aminoacid; Iridium; Ethylenic compound; Ruthenium complex; Conformation; Seven membered ring; Crystalline structure
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo701703e

Proline-derived peptide mimetics have become an area of paramount importance in peptide and protein chemistry. Since protein crystal structures frequently display Ψ angles of 140−170° 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 ΙΙ β-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 Ψ angles and thus can be exploited to probe molecular recognition and functional properties of biological systems.