| Carbohydrate-templated amino acids (CTAAs) have found their wide application in the synthesis of peptidomimetics and glycomimetics. Herein, we describe the design, synthesis and conformational properties of three new types of CTAAs: spirocyclic glucose-templated 3(S)-hydroxy- L-proline analogues (Glc(3S)-Hyp), glucose-templated D- and L-lysine analogues (GlcTk, GlcTK) and glucose-templated L-proline lysine hybrids (GlcTProLysHs). In order to explore the use of these building blocks in peptide chemistry all three CTAAs were incorporated into peptides or peptide mimics and the thermodynamic, kinetic and beta-turn-inducing properties were studied. These studies have resulted in the following observations and conclusions: (1) The studies of peptide mimics Ac-Glc(3S)-Hyp-OMe, Ac-Glc(3S)-Hyp-NHMe and tetrapeptides Ac-Leu-D-Phe-Glc(3 S)-Hyp-Val-NMe2 demonstrate that (5'R)-Glc(3 S)-Hyp increases the prolyl amide cis rotamer population with accelerated cis/trans isomerization kinetics in water and induces a type VIa beta-turn in the tetrapeptide when compared to unmodified reference peptides Ac-Pro-OMe, Ac-Pro-NHMe, Ac-(3S)-Hyp-OMe and Ac-(3S)-Hyp-NHMe. Whereas the diastereomer (5' S)-GlcTPro prefers the prolyl amide trans rotamer with a retarded cis/trans isomerization rate in water. ROESY and temperature coefficient experiments indicate that replacement of Pro with (5'S)-Glc(3S)-Hyp doesn't disturb the original conformation of the tetrapeptide. (2) Antibacterial in vitro tests of the dipeptides H2N-GlcTk-Tyr-OBn and H2N-GlcTk-Tyr-NHBn show that substitution of D-lysine by carbohydrate-templated-D-lysine analog GlcTk results in decreased antibacterial activity against Gram-positive and Gram-negative organisms. In addition, we discovered that the nature of the C-terminal substituent and the presence of hydrophobic moieties are crucial for antibacterial activity. (3) The conformational analysis of peptide mimics Ac-GlcTProLysHs-OMe (NHMe) demonstrate that unnatural, high lysyl cis amide rotamer populations can be achieved. This enables peptide chemists now to explore the biological implications of the lysyl cis amide population in lysine-rich antimicrobial peptides and other peptides. |
