Selina Hollstein

Nature Chemistry, Published online: 18 November 2019; doi:10.1038/s41557-019-0375-x

Communications Chemistry, Published online: 06 September 2019; doi:10.1038/s42004-019-0207-3

Small pseudopeptidic cages show enhanced chloride binding and transport across a lipid membrane at acidic pH. This increases their cytotoxicity towards lung adenocarcinoma cells in environments mimicking those surrounding solid tumors.

Abstract

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage‐like anionophores displaying pH‐dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H⁺/Cl⁻ 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 towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino‐acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs.

An off and on relationship: In strongly acidic aqueous solutions, the oxime bond is dynamic and allows both a catenane and a macrocycle to self‐assemble in relatively high yields. The dynamic nature of oxime linkage could be turned OFF almost fully in neutral conditions, making the self‐assembled catenane kinetically inert in both solid state and solution at elevated temperatures or during chromatography and counteranion exchange.

Abstract

Oxime, whose dynamic nature was reported to be switchable between ON/OFF by tuning the acidity, is employed in a novel type of dynamic covalent approach that is amenable to use in water for self‐assembly of purely organic molecules with complex topology. In strongly acidic conditions, the dynamic nature of oxime is turned ON, allowing occurrence of error‐checking and therefore a catenane and a macrocycle self‐assembled in high yields. In neutral conditions, oxime ceases to be dynamic, which helps to trap the self‐assembled products even when the driving forces of their formation are removed. We envision that this switchable behaviour might help, at least partially, to resolve a commonly encountered drawback of dynamic covalent chemistry, namely that the intrinsic stability of the self‐assembled products containing dynamic bonds, such as imine or hydrazone, are often jeopardized by their reversible nature.