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Indoloazepinone‐Constrained Oligomers as Cell‐Penetrating and Blood–Brain‐Barrier‐Permeating Compounds
Author(s) -
Van der Poorten Olivier,
Legrand Baptiste,
Vezenkov Lubomir L.,
GarcíaPindado Júlia,
Bettache Nadir,
Knuhtsen Astrid,
Pedersen Daniel Sejer,
SánchezNavarro Macarena,
Martinez Jean,
Teixidó Meritxell,
Garcia Marcel,
Tourwé Dirk,
Amblard Muriel,
Ballet Steven
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700678
Subject(s) - circular dichroism , chemistry , stereochemistry , biophysics , in vitro , indole test , oligomer , permeation , crystallography , membrane , biochemistry , polymer chemistry , biology
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.