Exploiting Aromatic Interactions for β‐Peptide Foldamer Helix Stabilization: A Significant Design Element

Abstract

Tetrameric H10/12 helix stabilization was achieved by the application of aromatic side-chains in β-peptide oligomers by intramolecular backbone-side chain CH-π interactions. Because of the enlarged hydrophobic surface of the oligomers, a further aim was the investigation of the self-assembly in a polar medium for the β-peptide H10/12 helices. NMR, ECD, and molecular modeling results indicated that the oligomers formed by cis-[1S,2S]- or cis-[1R,2R]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (ATENAC) and cis-[1R,2S]- or cis-[1S,2R]-2-aminocyclohex-3-enecarboxylic acid (ACHEC) residues promote stable H10/12 helix formation with an alternating backbone configuration even at the tetrameric chain length. These results support the view that aromatic side-chains can be applied for helical structure stabilization. Importantly, this is the first observation of a stable H10/12 helix with tetrameric chain-length. The hydrophobically driven self-assembly was achieved for the helix-forming oligomers, seen as vesicles in transmission electron microscopy images. The self-association phenomenon, which supports the helical secondary structure of these oligomers, depends on the hydrophobic surface area, because a higher number of aromatic side-chains yielded larger vesicles. These results serve as an essential element for the design of helices relating to the H10/12 helix. Moreover, they open up a novel area for bioactive foldamer construction, while the hydrophobic area gained through the aromatic side-chains may yield important receptor-ligand interaction surfaces, which can provide amplified binding strength.

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos

“…Among the secondary structures, hydrogen bonding between carbonyl oxygen and the amino group of every third residue in the helical turn stabilizes an α-helix (each helical turn consisting of 3.6 amino acid residues) while βsheets originate with hydrogen bonding between two or more β-strands (along which, the backbone of the peptide stretches) (Kulkarni et al, 2019). The self-association phenomenon of aromatic side-chains in β-peptide oligomers supports the helical secondary structure formed by intramolecular backbone-side chain CH-π interactions and yields large vesicles due to the gain in the hydrophobic area (Mándity et al, 2014). In a study, Sarkar et al (2015) have also demonstrated the effect of solvent interactions on the folding pattern resulting in a change in initial helical conformation and structural diversity of short aromatic γpeptides.…”

Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

“…[22] Finally,t his C À Hc arbamoylation method was applied to the synthesis of the enantiopure free b-lactam 4ac and baminoacid 5ac.T he latter,which was previously obtained by enzymatic resolution, is of high interest for the synthesis of bpeptides (Scheme 5). [23] Commercially available enantiopure tetrahydronaphthylamine 3ac was converted into carbamoyl chloride 1ac,w hich underwent CÀHc arbamoylation under the optimal COgen conditions to give TMB-protected blactam 2ac in 82 %y ield. Persulfate-mediated oxidative cleavage provided b-lactam 4ac,w hich underwent acidic hydrolysis to give (+ +)-5ac in very good overall yield (64 %for 5steps).…”

Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

“…Although levels of enantioselectivity higher than 92:8 could not be reached, this result constitutes ap roof-of-concept enantioselective synthesis of b-lactams through the desymmetrization of unactivated methyl groups,w hich is to date unprecedented. [23] Commercially available enantiopure tetrahydronaphthylamine 3ac was converted into carbamoyl chloride 1ac,w hich underwent CÀHc arbamoylation under the optimal COgen conditions to give TMB-protected blactam 2ac in 82 %y ield. [22] Finally,t his C À Hc arbamoylation method was applied to the synthesis of the enantiopure free b-lactam 4ac and baminoacid 5ac.T he latter,which was previously obtained by enzymatic resolution, is of high interest for the synthesis of bpeptides (Scheme 5).…”