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Design, Synthesis, and NMR Structure of Linear and Cyclic Oligomers Containing Novel Furanoid Sugar Amino Acids
Author(s) -
Gruner Sibylle A. W.,
Truffault Vincent,
Voll Georg,
Locardi Elsa,
Stöckle Matthias,
Kessler Horst
Publication year - 2002
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20021004)8:19<4365::aid-chem4365>3.0.co;2-u
Subject(s) - chemistry , oligomer , amino acid , stereochemistry , butyric acid , peptidomimetic , peptide , circular dichroism , organic chemistry , biochemistry
Sugar Amino Acids (SAAs) are sugar moieties containing at least one amino and one carboxyl group. The straightforward synthesis of two furanoid SAAs, 3‐amino‐3‐deoxy‐1,2‐isopropylidene‐ α ‐ D ‐ribofuranoic acid (f‐SAA 1 ) and 3‐amino‐3‐deoxy‐1,2‐isopropylidene‐ α ‐ D ‐allofuranoic acid (f‐SAA 2 ) starting from diacetone glucose, is described. These SAAs were used as structural templates aiming at new structures for peptidomimetic drug design. f‐SAA 1 resembles a β ‐amino acid, whereas f‐SAA 2 is a γ ‐amino acid mimetic. Thus, for the synthesis of the mixed, linear and cyclic oligomers of f‐SAA 1 , β ‐homo‐glycine ( β ‐hGly, also called β ‐alanine) was chosen as an amino acid counterpart, while for the oligomer of f‐SAA 2 γ ‐amino butyric acid (GABA) was chosen. Fmoc‐[f‐SAA 1 ‐ β ‐hGly] 3 ‐OH ( 3 ) and cyclo[f‐SAA 1 ‐ β ‐hGly] 3 ( 5 ) resemble linear and cyclic β ‐peptides with a very different substitution pattern, compared with the β ‐peptides known so far in the literature, whereas Fmoc‐[f‐SAA 2 ‐GABA] 3 ‐OH ( 4 ) resembles a γ ‐peptide. The linear f‐SAA oligomers 3 and 4 were synthesized on the solid‐phase using Fmoc strategy. 23 unambiguous interresidue NOE contacts (from a total of 76 NOE values), obtained from extensive NMR studies in C 3 CN, were used in subsequent simulated annealing and MD calculations, to elucidate the 12/10/12‐helical structure of oligomer 3 in CH 3 CN. The results indicate that f‐SAA 1 strongly induces a secondary structure. A characteristic CD curve for the linear oligomer 3 is observed up to 75 °C in both CH 3 CN and CH 3 CN/H 2 O, even though 3 contains β ‐hGly, which is known to destabilize helices. By contrast, 4 does not seem to form a stable conformation in solution. The cyclic SAA containing oligomer cyclo [f‐SAA 1 ‐ β ‐hGly] 3 ( 5 ) exhibits a C 3 symmetric conformation on the NMR chemical shift time scale.