pH‐Dependent Chloride Transport by Pseudopeptidic Cages for the Selective Killing of Cancer Cells in Acidic Microenvironments

Abstract

Acidic microenvironments in solid tumors are ah allmark of cancer.I nspired by that, we designed af amily of pseudopeptidic cage-like anionophores displaying pHdependent activity.W hen protonated, they efficiently bind chloride anions.T hey also transport chloride through lipid bilayers,with their anionophoric properties improving at acidic pH, suggesting an H + /Cl À symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase.The chloride affinity and the chloride-exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towardsl ung adenocarcinoma cells at the pH of the microenvironment of as olid tumor.T hese properties depend on the nature of the aminoacid side chains of the cages,whichmodulate their lipophilicity and interactions with the cell membrane.T his paves the way towards using pH as ap arameter to control the selectivity of cytotoxic ionophores as anticancer drugs.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Self‐Assembled Artificial Ion‐Channels toward Natural Selection of Functions

“…Kobuke, [118] Matile [119] and Hou [120] reported synthetic macrodipole or charged superstructures for voltage sensors. Although reports about completely self‐assembled supramolecular channel with pH‐responsiveness are limited, there are already synthetic carriers available that exhibit proton‐gated behavior, like pseudopeptidic cage reported by Alfonso group, [121] phenylthiosemicarbazone [71] and thiosquaramide, [66] reported by Gale group, or bis(sulfonamide)‐based carrier [58] reported by Talukdar group. Ligand internalization is another internal stimulus to trigger ion transport through assembled channels.…”

Selbstorganisierte künstliche Ionenkanäle für die natürliche Selektion von Funktionen

“…Obwohl die Forschungsarbeiten über vollständig selbstaggregierte supramolekulare Kanäle mit pH‐Ansprechen beschränkt sind, sind bereits synthetische Träger verfügbar, die protonengeschaltetes Verhalten zeigen, wie z.B. ein Pseudopeptid‐Käfig, der von der Arbeitsgruppe von Alfonso beschrieben wurde, [121] Phenylthiosemicarbazon [71] und Thiosquaramid, [66] die von der Arbeitsgruppe von Gale beschrieben wurden, oder ein Träger auf Bis(sulfonamid)‐Basis, [58] der von der Arbeitsgruppe von Talukdar beschrieben wurde. Ein weiterer interner Stimulus zum Auslösen von Ionentransport durch zusammengesetzte Kanäle ist die Internalisierung von Liganden.…”

Fluorescent Molecular Cages with Sucrose and Cyclotriveratrylene Units for the Selective Recognition of Choline and Acetylcholine

“…The synthesis of molecular cages is particularly attractive due to its selective recognition properties. 5 These receptors can find application as catalysts, 6 separators, 7 sensors, 8 porous materials, 9 polymers, 10 transporters, 11 or drug delivery systems. 12 Among them, cryptophanes and hemicryptophanes are of particular interest as they are able to recognize small organic compounds.…”