Indoloazepinone-Constrained Oligomers as Cell-Penetrating and Blood-Brain-Barrier-Permeating Compounds

Chembiochem. 2018 Apr 4;19(7):696-705. doi: 10.1002/cbic.201700678. Epub 2018 Feb 28.

Abstract

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 by circular dichroism (CD) and NMR spectroscopy. Whereas Boc-[l-Aia-Gly]2,4 -OBn oligomers 12 and 13 and Boc-[l-Aia-β3 -h-l-Ala]2,4 -OBn oligomers 16 and 17 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 π-stacking interactions involving the indole rings of the four l-Aia residues forming a dense hydrophobic cluster. All of the proposed FITC-6-Ahx-[l-Aia-Xxx]4 -NH2 oligomers 19-23, with the exception of FITC-6-Ahx-[l-Aia-Gly]4 -NH2 (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg8 . In parallel, the compounds of this series were successfully explored in an in vitro blood-brain barrier (BBB) permeation assay. Although 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.

Keywords: aminoindoloazepinones; blood-brain barrier; cell-penetrating peptides; drug delivery; peptidomimetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / chemical synthesis
  • Azepines / metabolism*
  • Azepines / toxicity
  • Blood-Brain Barrier / metabolism*
  • Cattle
  • Cell Line, Tumor
  • Cell Membrane / metabolism*
  • Cell Membrane Permeability
  • Cell-Penetrating Peptides / chemical synthesis
  • Cell-Penetrating Peptides / metabolism*
  • Cell-Penetrating Peptides / toxicity
  • Drug Carriers / chemical synthesis
  • Drug Carriers / metabolism*
  • Drug Carriers / toxicity
  • Humans
  • Indoles / chemical synthesis
  • Indoles / metabolism*
  • Indoles / toxicity
  • Molecular Conformation
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / metabolism
  • Peptidomimetics / toxicity

Substances

  • Azepines
  • Cell-Penetrating Peptides
  • Drug Carriers
  • Indoles
  • Peptidomimetics