Chembiochem. 2018 Jan 29. doi: 10.1002/cbic.201700678. [Epub ahead of print]
Van der Poorten O, Legrand B, Vezenkov L, Garcia-Pindado J, Bettache N, Knuhtsen A, Sejer Pedersen D, Sanchez-Navarro M, Martinez J, Teixido M, Garcia M, Tourwe D, Amblard M, Ballet S.
Non-cationic and amphipathic indoloazepinone-constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [L-Aia-Xxx]n oligomers were investigated using circular dichroism and NMR spectroscopy. While Boc-[L-Aia-Gly]2,4-OBn 12-13 and Boc-[L-Aia-β3-h-L-Ala]2,4-OBn 16-17 oligomers were totally or partially disordered, Boc-[L-Aia-L-Ala]2-OBn 14 induced a typical turn stabilized by C5- and C7-membered H-bond pseudo-cycles and aromatic interactions. Boc-[L-Aia-L-Ala]4-OBn 15 exhibited a unique structure with remarkable T-shaped pie-stacking interactions involving the indole rings of the four L-Aia residues forming a dense hydrophobic cluster. All the proposed FITC-6-Ahx-[L-Aia-Xxx]4-NH2 oligomers 19-23, with exception of FITC-6-Ahx-[L-Aia-Gly]4-NH2 oligomer 18, were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg8. In parallel, this series of compounds was successfully explored on an in vitro blood-brain barrier (BBB) permeation assay. While no passive diffusion permeability was observed for any of the tested Ac-[L-Aia-Xxx]4-NH2 oligomers in the PAMPA model, Ac-[L-Aia-L-Arg]4-NH2 26 showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell-penetration.