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Issue 9, 2020
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Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl channel

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Abstract

Synthetic transmembrane ion transport systems are emerging as new tools for anticancer therapy. Here, a series of 2-hydroxy-N1,N3-diarylisophthalamide-based fluorescent ion channel-forming compounds are reported. Ion transport studies across large unilamellar vesicles confirmed that the compound with two 3,5-bis(trifluoromethyl)phenyl arms is the most efficient transporter among the series and it facilitates M+/Cl symport. The compound formed supramolecular ion channels with a single-channel conductance of 100 ± 2 pS, a diameter of 5.06 ± 0.16 Å and a permeability ratio, PCl/PK+, of 8.29 ± 1. The molecular dynamics simulations of the proposed M2.11 channel (i.e. 11 coaxial layers of a dimeric rosette) with K+ and Cl in the preequilibrated POPC lipid bilayer with water molecules illustrated various aspects of channel formation and ion permeation. Cell viability assay with the designed compounds indicated that cell death is being induced by the individual compounds which follow the order of their ion transport activity and chloride and cations play roles in cell death. The inherent fluorescence of the most active transporter was helpful to monitor its permeation in cells by confocal microscopy. The apoptosis-inducing activity upon perturbation of intracellular ionic homeostasis was established by monitoring mitochondrial membrane depolarization, generation of reactive oxygen species, cytochrome c release, activation of the caspase 9 pathway, and finally the uptake of the propidium iodide dye in the treated MCF7 cells.

Graphical abstract: Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl− channel

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Supplementary files

Article information


Submitted
24 Dec 2019
Accepted
16 Jan 2020
First published
29 Jan 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 2420-2428
Article type
Edge Article

Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl channel

J. A. Malla, R. M. Umesh, A. Vijay, A. Mukherjee, M. Lahiri and P. Talukdar, Chem. Sci., 2020, 11, 2420
DOI: 10.1039/C9SC06520B

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