Chirality and template-mediated induction of helical preferences in achiral ß-peptides.

This study describes chirality- or template-mediated helical induction in achiral ß-peptides for the first time. A strategy of end capping ß-peptides derived from ß-hGly (the smallest achiral ß-amino acid) with a chiral ß-amino acid that possesses a carbohydrate side chain (ß-Caa; C-linked carbo ß-amino acid) or a small, robust helical template derived from ß-Caas, was adopted to investigate folding propensity. A single chiral (R)-ß-Caa residue at the C- or N-terminus in these oligomers led to a preponderance of right-handed 12/10-helical folds, which was reiterated more strongly in peptides capped at both the C- and N-terminus. Likewise, the presence of a template (a 12/10-helical trimer) at both the C- and N-terminus resulted in a very robust helix. The propagation of the helical fold and its sustenance was found in a homo-oligomeric sequence with as many as seven ß-hGly residues. In both cases, the induction of helicity was stronger from the N terminus, whereas an anchor at the C terminus resulted in reduced helical propensity. Although these oligomers have been theoretically predicted to favor a 12/10-mixed helix in apolar solvents, this study provides the first experimental evidence for their existence. Diastereotopicity was found in both the methylene groups of the ß-hGly moieties due to chirality. Additionally, the ß-hGly units have shown split behavior in the conformational space to accommodate the 12/10-helix. Thus, end capping to assist chiralty- or template-mediated helical induction and stabilization in achiral ß-peptides is a very attractive strategy.

Synthesis of beta-peptides with beta-helices from new C-linked carbo-beta-amino acids: study on the impact of carbohydrate side chains.

The design and synthesis of beta-peptides from new C-linked carbo-beta-amino acids (beta-Caa) presented here, provides an opportunity to understand the impact of carbohydrate side chains on the formation and stability of helical structures. The beta-amino acids, Boc-(S)-beta-Caa((g))-OMe 1 and Boc-(R)-beta-Caa((g))-OMe 2, having a D-galactopyranoside side chain were prepared from D-galactose. Similarly, the homo C-linked carbo-beta-amino acids (beta-hCaa); Boc-(S)-beta-hCaa((x))-OMe 3 and Boc-(R)-beta-hCaa((x))-OMe 4, were prepared from D-glucose. The peptides derived from the above monomers were investigated by NMR, CD, and MD studies. The beta-peptides, especially the shorter ones obtained from the epimeric (at the amine stereocenter C(beta)) 1 and 2 by the concept of alternating chirality, showed a much smaller propensity to form 10/12-helices. This substantial destabilization of the helix could be attributed to the bulkier D-galactopyranoside side chain. Our efforts to prepare peptides with alternating 3 and 4 were unsuccessful. However, the beta-peptides derived from alternating geometrically heterochiral (at C(beta)) 4 and Boc-(R)-beta-Caa((x))-OMe 5 (D-xylose side chain) display robust right-handed 10/12-helices, while the mixed peptides with alternating 4 and Boc-beta-hGly-OMe 6 (beta-homoglycine), resulted in left-handed beta-helices. These observations show a distinct influence of the side chains on helix formation as well as their stability.

Synthesis and conformational studies of peptides from new C-linked carbo-beta-amino acids (beta-Caas) with anomeric methylamino- and difluorophenyl moieties.

New C-linked carbo-beta-amino acids (beta-Caas), Cbz-(S)-beta-Caa-(NHBoc)-OMe (1) and Cbz-(R)-beta-Caa-(NHBoc)-OMe (2), with an additional amine group (methylamino group of NHBoc) at the C-1 position of the lyxofuranoside side chain and Boc-(S)-beta-Caa-(diFP)-OMe (3) and Boc-(R)-beta-Caa-(diFP)-OMe (4), with a C-difluorophenyl (diFP) moiety at the anomeric position of the lyxofuranoside side chain were prepared from D-mannose. Beta-peptides [tetra- and hexapeptides] were synthesized from these beta-Caas, 'epimeric' [at the amine stereocentre (C(beta))], using the concept of 'alternating chirality' to carry out their conformational studies [NMR (CDCl(3)), CD and MD]. In the monomer design, it was envisaged that the presence of an additional amine group in 1 or 2 would help in solubilizing the peptides in water, while, the C-difluorophenyl (diFP) moiety of 3 and 4 is expected to enhance the biological activity. The peptides having 1 and 2, though could not retain their 12-10-mixed helices in water, have shown moderate activity against gram positive and gram negative bacterial strains. The peptides prepared from 3 and 4, much against our expectations, did not display any biological activity.

12/10- and 11/13-mixed helices in alpha/gamma- and beta/gamma-hybrid peptides containing C-linked carbo-gamma-amino acids with alternating alpha- and beta-amino acids.

New classes of alpha/gamma- and beta/gamma-hybrid peptides have been synthesized with novel 12/10- and 11/13-mixed helical patterns, respectively. The alpha/gamma-peptides were derived from the dipeptide repeats with alternating arrays of l-Ala and gamma-Caa((l)) (C-linked carbo-gamma-amino acid from d-mannose), which generated a new 12/10-mixed helix, for the first time, without a beta-amino acid. The beta/gamma-peptides made from an alternating arrangement of beta-Caa((x)) (C-linked carbo-beta-amino acid) and gamma-Caa((x)) (C-linked carbo-gamma-amino acid from d-xylose), on the other hand, resulted in an unprecedented 11/13-helix. The secondary structures in these peptides have been ascertained from detailed NMR studies, and CD spectroscopy and molecular dynamics investigations provided additional support for the structures derived.