Tuning of the prolyl trans/cis-amide rotamer population by use of C-glucosylproline hybrids.
We describe the synthesis of a fused bicyclic C-glucosylproline hybrid (GlcProH) from commercially available 2,3,4,6-tetra-O-benzyl-d-glucopyranose. The GlcProH was incorporated into the model peptides Ac-GlcProH-NHMe and Ac-Gly-GlcProH-NHMe. Postsynthetic modifications can be introduced via derivatization of the carbohydrate scaffold. Conformational analysis of the GlcProH-modified model peptides shows that while the conformation of GlcProH remains fixed, the prolyl N-terminal amide equilibrium (Kt/c) can be varied with different modifications of the carbohydrate scaffold. Simple N-acyl derivatives studied by NMR spectroscopy showed that in CD3OD there was an increase in the cis-amide content as the sugar substituents changed from benzyl (10%) to hydroxyl (22%) to acetate (36%). Similar effects were observed in DMSO-d6. The exact nature of the influence is unclear, but it most likely arises through intramolecular interactions between sugar groups and the peptidic amide backbone. Overall, our GlcProH demonstrates variation in Kt/c through tuning of the carbohydrate scaffold: a new concept in proline peptidomimetics.
Owens
Neil W
NW
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada.
Braun
Craig
C
Schweizer
Frank
F
D000577:Amides / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry; D004987:Ethers / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006031:Glycosylation; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D012997:Solvents; D013237:Stereoisomerism
D000577:Amides; D002264:Carboxylic Acids; D004987:Ethers; D012997:Solvents; D005461:Fluorine; D011392:Proline; D005947:Glucose