Indoloazepinone‐Constrained Oligomers as Cell‐Penetrating and Blood–Brain‐Barrier‐Permeating Compounds |
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| Authors: | Olivier Van der Poorten Dr. Baptiste Legrand Dr. Lubomir L. Vezenkov Dr. Júlia García‐Pindado Dr. Nadir Bettache Dr. Astrid Knuhtsen Prof. Dr. Daniel Sejer Pedersen Dr. Macarena Sánchez‐Navarro Prof. Dr. Jean Martinez Dr. Meritxell Teixidó Dr. Marcel Garcia Prof. Dr. Dirk Tourwé Dr. Muriel Amblard Dr. Steven Ballet |
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| Affiliation: | 1. Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium;2. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, Montpellier, Cedex 5, France;3. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain;4. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark |
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| 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. |
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| Keywords: | aminoindoloazepinones blood– brain barrier cell-penetrating peptides drug delivery peptidomimetics |
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