Preparation and conformational analysis of vancomycin hexapeptide and aglucovancomycin hexapeptide

Abstract

The preparations of the hexapeptides (3) and (6) derived from the antibiotic vancomycin (1)' are described. The conformation of the N-terminal regions of (3) and (6) are discussed and compared t o previous observations made on vancomycin. The hexapeptides lack any significant binding capability relative to vancomycin, and the reasons for this are discussed.

Structural modifications of glycopeptide antibiotics

“…The activity of TDHPA was unexpected considering that the vancomycin-derived hexapeptide aglycone VAHP was devoid of antibacterial activity. 24,47,84 This is likely due to the different conformation of the hexapeptide backbone in the active site region. While TDHPA nearly maintains the original conformation of the peptide chain and in particular the orientation of the 2,3-amides at TD, in VAHP, the 2,3-trans peptide unit exhibit a 180Њ flipping…”

“…23 and 24) of the dalbaheptide family, such as vancomycin (V), ristocetin (R), ‡ ‡ and A-40,926 (A-40) underwent reductive hydrolysis of the heptapeptide backbone in the same position as in teicoplanins. In contrast antibiotic A-42,867 87 and des(N-methyl-Leu)-vancomycin (namely vancomycin hexapeptide, VHP), 24,47,84,88 which showed conformational changes in their peptide backbone relative to vancomycin, were resistant. Based on these findings, a possible reductive hydrolysis mechanism was conceived (Chart 1) which is strictly related to the particular conformation of the heptapep- Data adapted from Ref.…”

“…Chemical (Edman degradation) 24,47,84 and biological 48 methods for the removal amino acid 1 of vancomycin have been reported. The methods used for removal of amino acid 1 could not be used for removal of amino acid 3 in vancomycin.…”

“…24,47,84 Both of these hexapeptides are useful intermediates for the preparation of new structurally novel dalbaheptides. In particular, from VAHP there is the possibility of obtaining a number of VA-derived glycopeptides by direct condensation of the terminal amino group with a series of different amino acids.…”

Vancomycin: ligand recognition, dimerization and super‐complex formation

“…For example, NMR studies [4,5,24] suggest that there are small but significant differences between the structure found in the crystal and that in solution; in particular in the orientation of HDPY2 and ASN3, potentially affecting both ligand binding and dimerization. Furthermore, although it is clear that vancomycin primarily forms back-to-back dimers in solutions, evidence suggests that face-to-face dimer and higher order oligomers may be functionally important.…”