Solid-Phase Synthesis of Water-Soluble Helically Folded Hybrid α-Amino Acid/Quinoline Oligoamides

Abstract

We report here a solid phase synthesis methodology that allows the incorporation of α-amino acids (X) into quinoline (Q) oligoamide foldamer sequences. Water-soluble hybrid oligoamides based on the XQ2 trimer repeat motif were shown to adopt helical conformations presenting α-amino acid side chains in a predictable linear array on one face of the helix. In contrast, sequences based on the XQ dimer motif expressed less well-defined behavior, most likely due to local conformational variability precluding long-range order. Also presented is a full structural investigation by NMR of a dodecameric XQ2-type foldamer containing four different amino acid residues (Lys, Ala, Asp, and Ser).

Ribosomal Incorporation of Aromatic Oligoamides as Peptide Sidechain Appendages

“…Capitalizing on the even greater tolerance of the ribosome during translation initiation, exotic peptides, terpenes and, recently, non‐amino acid substrates and aromatic oligoamide foldamers, have been incorporated as the first unit of ribosomal peptide synthesis to produce various types of hybrid molecules . Because of their strong propensity to adopt helical conformations, aromatic foldamers may transmit folding information to the peptide and control its conformation . With masses up to 1 kDa, they constitute the bulkiest and most rigid objects ever incorporated by the translation machinery, including delivery to the ribosome and passage through its exit tunnel.…”

Solid Phase Synthesis of Helically Folded Aromatic Oligoamides

“…In contrast, hybrids based on an XQ dimer repeat motif were 7 found to adopt a partially folded zig-zag tape conformation with local conformational variability precluding long range order. This behavior was also evident in protic solvents, where the increased solvent-accessibility of the hydrophobic aromatic surfaces appeared to drive nonspecific aggregation at lower temperatures (Hu et al, 2016;Kudo, Maurizot, Masu, Tanatani, & Huc, 2014) Acetyl chloride, acetic anhydride, CaH2, CBr4, 1-chloro-N,N,2-trimethyl-1-propenylamine…”

“…We recently reported examples of this kind using helically folded quinoline oligoamides. Sequences combining -amino acid (X) and quinoline (Q) units together in an XQ2 trimer repeat motif ( Figure 3) were found to adopt a single well-defined canonical aromatic helical conformation in both organic and aqueous conditions (Kudo, Maurizot, Kauffmann, Tanatani & Huc, 2013;Hu, Dawson, Kudo, Nagaoka, Tanatani & Huc, 2016). In contrast, hybrids based on an XQ dimer repeat motif were 7 found to adopt a partially folded zig-zag tape conformation with local conformational variability precluding long range order.…”

Foldamers in Medicinal Chemistry

“…Water-soluble α-amino acid/quinoline oligoamides have thus been designed in order to form a linear array of proteinogenic side chains on one face of the helix. [57] To perform the synthesis of such hybrid sequences, a powerful solid phase synthesis strategy has been developed via the in situ formation of amino acid chlorides.…”