Host-guest complexation of APP with cucurbit[7]uril. Theoretical and experimental studies on the supramolecular inhibition of its cytotoxicity on SERT

The supramolecular binding behavior of the fluorescent compound 4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP + ) and CB[7] was investigated in aqueous solution by nuclear magnetic resonance, isothermal titration calorimetry, high-resolution mass spectrometry, UV-Vis spectroscopy, steady-state...

Full description

Saved in:
Bibliographic Details
Published in:New journal of chemistry 2022-08, Vol.46 (32), p.15732-15739
Main Authors: Almendras, Sebastián, Zárate, Ana María, Dinamarca-Villarroel, Luis, Guerra, Daniel, Fuentealba, Denis, Eltit, Jose M, Aliaga, Margarita E, Fierro, Angélica, Pérez, Edwin G
Format: Article
Language:English
Subjects:
Aqueous solutions
Binding
Chemical compounds
Complexation
Cytotoxicity
Fluorescence
Mass spectrometry
Modelling
NMR
Nuclear magnetic resonance
Serotonin
Stoichiometry
Titration calorimetry
Toxicity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The supramolecular binding behavior of the fluorescent compound 4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP + ) and CB[7] was investigated in aqueous solution by nuclear magnetic resonance, isothermal titration calorimetry, high-resolution mass spectrometry, UV-Vis spectroscopy, steady-state and time-resolved fluorescence spectroscopy, and molecular modelling. APP + binds to CB[7] with a binding constant ( K b ) of (2.6 ± 0.3) × 10 6 M −1 , with a 1 : 1 inclusion stoichiometry. APP + was shown to be cytotoxic towards HEK293 cells expressing human serotonin transporter (hSERT), with an IC 50 of 0.146 μM. Meanwhile, this compound did not show any cytotoxicity towards wild type HEK293 cells. Moreover, cell uptake through the hSERT was consistent with the inhibition of cytotoxicity by fluoxetine, which binds tightly to the transporter. Interestingly, cytotoxicity could also be inhibited by the pre-incubation treatment of the cells with CB[7] suggesting a protective role for this macrocycle due to the complexation of APP + . Finally, molecular modelling studies suggest a blocker effect generated by the CB[7]/APP + complex on SERT preventing the entrance of APP + . The supramolecular binding behavior of APP + and CB[7] in aqueous solution was studied by different techniques. APP + showed cytotoxicity towards HEK293 cells expressing hSERT. This cytotoxicity was inhibited by the treatment of the cells with CB[7].
ISSN:1144-0546
1369-9261
DOI:10.1039/d2nj01963a