M. Cudic et al., SYNTHESIS AND CIS-TRANS ISOMERISM IN NOVEL LEU-ENKEPHALIN-RELATED PEPTIDOMIMETICS CONTAINING N-GLYCATED GLYCINE RESIDUES, Journal of the Chemical Society. Perkin transactions. I, (11), 1998, pp. 1789-1795
The influence of a new peptoid residue on amide-bond stereochemistry h
as been explored via the synthesis and NMR analysis of novel peptidomi
metics related to the endogenous opioid pentapeptide Leuenkephalin (H-
Tyr-Gly-Gly-Phe-Leu-OH), The compounds studied include protected and u
nprotected enkephalin analogues N-alkylated at either the second (Gly(
2)) or both the second and the third (Gly(2),Gly(3)) amino acid residu
es with a 6-deoxy-D-galactose moiety, The syntheses of the mono-(7) an
d the bis-glycated pentapeptide (11) were performed in a stepwise mann
er in solution by employing N-glycated glycine as the building block.
The relative populations of the cis and trans isomers in the compounds
studied were estimated by NMR spectroscopy In the fully protected N-g
lycated dipeptide 3 the most abundant isomer (64%) was shown to contai
n a cis Tyr(1)-(X)Gly(2) amide bond. NMR analysis of mono-N-glycated p
entapeptide 6 provided evidence that elongation of the peptide chain d
isfavours the cis and augments the trans isomer population (cis: trans
35:65), For the unprotected monoglycated peptides 5 and 7 both the a-
and P-pyranose forms of the galactose moieties were detected, the B-py
ranose tautomer being the most abundant (similar to 70%). Removal of t
he protecting groups decreased the proportion of cis-rotamers relative
to the corresponding protected peptides 3 and 6, The NMR spectra of e
nkephalin-related peptides 8-11, which contain two N-glycated glycine
residues, were extremely complex; both proximal and distal isomerizati
on effects were observed. For the bis-glycated tripeptide 8 significan
t amounts of both the cis and trans rotamers were observed for the Tyr
(1)-(X)Gly(2) and (X)Gly(2)-(X)Gly(3) peptide bonds. In the fully prot
ected pentapeptide 10 the configurational equilibrium was markedly shi
fted in favour of the trans isomers; only 15% of the cis isomer was ob
served for the Tyr(1)-(X)Gly(2) bond, whereas the (X)Gly(2)-(X)Gly(3)
bond was completely in the trans configuration.