Nanosized hybrid oligoamide foldamers: aromatic templates for the folding of multiple aliphatic units

Oligoamide sequences comprised of both 8-amino-2-quinolinecarboxylic acid "Q" and 6-aminomethyl-2-pyridinecarboxylic acid "P" have been synthesized. It was found that the aliphatic amine of P greatly facilitates amide couplings, as opposed to the aromatic amine of Q, which enabled us to prepare sequences having up to 40 units. The conformation and conformational stability of these oligomers were characterized in the solid state using X-ray crystallography and in solution using NMR and various chromatographic techniques. Q(n) oligomers adopt very stable helically folded conformations whereas P(n) oligomers do not fold and impart conformational preferences distinct from those of Q units. When a P(n) segments is attached at the end of a Q(4) segment, a couple P units appear to follow the folding pattern imposed by the Q(n) segment, but P units remote from the Q(n) segment do not fold. When a P(n) segment is inserted between two Q(4) segments, the P(n) segment adopts the canonical helical conformation imposed by the Q units at least up to two full helical turns (n = 5). However, the overall stability of the helix tends to decrease as the number of P units increases. When noncontiguous P units separated by Q(4) segments are incorporated in a sequence, they all adopt the helical conformation imposed by Q monomers and the overall helix stability increases when helix length increases. For example, a 40mer with a sequence (PQ(4))(8) folds into a rod-like helix spanning over 16 turns with a length of 5.6 nm. This investigation thus demonstrates that remarkably long (nanometers) yet well-defined foldamers can be efficiently synthesized stepwise and that their helical stability may be continuously tuned upon controlling the ratio and sequence of P and Q monomers.