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

TY - JOUR

T1 - Indoloazepinone-Constrained Oligomers as Cell-Penetrating and Blood-Brain-Barrier-Permeating Compounds

AU - Van Der Poorten, Olivier

AU - Legrand, Baptiste

AU - Vezenkov, Lubomir L.

AU - García-pindado, Júlia

AU - Bettache, Nadir

AU - Knuhtsen, Astrid

AU - Pedersen, Daniel Sejer

AU - Sánchez-navarro, Macarena

AU - Martinez, Jean

AU - Teixidó, Meritxell

AU - Garcia, Marcel

AU - Tourwé, Dirk

AU - Amblard, Muriel

AU - Ballet, Steven

PY - 2018/4/4

Y1 - 2018/4/4

N2 - 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-β 3 -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 C 5 - and C 7 -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 -NH 2 oligomers 19–23, with the exception of FITC-6-Ahx-[l-Aia-Gly] 4 -NH 2 (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg 8 . 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 -NH 2 oligomers in the PAMPA model, Ac-[l-Aia-l-Arg] 4 -NH 2 (26) showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell penetration.

AB - 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-β 3 -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 C 5 - and C 7 -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 -NH 2 oligomers 19–23, with the exception of FITC-6-Ahx-[l-Aia-Gly] 4 -NH 2 (18), were internalized by MDA-MB-231 cells with higher efficiency than the positive references penetratin and Arg 8 . 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 -NH 2 oligomers in the PAMPA model, Ac-[l-Aia-l-Arg] 4 -NH 2 (26) showed significant permeation in the in vitro cell-based human model of the BBB, suggesting an active mechanism of cell penetration.

U2 - 10.1002/cbic.201700678

DO - 10.1002/cbic.201700678

M3 - Journal article

C2 - 29377388

SN - 1439-4227

VL - 19

SP - 696

EP - 705

JO - ChemBioChem

JF - ChemBioChem

IS - 7

ER -