Fluorinated bisbenzimidazoles were synthesized as a new class of drug-like anion transporters with chloride-mediated, cell apoptosis-inducing activity.

No abstract

Chloride is the most abundant anion in living systems. Most natural or synthetic chloride anionophores function by hydrogen-bonding interactions. However, dynamic metal-anion coordination can also be an efficient way for transporting chloride across membranes as well. Here we investigate anion transport by manganese(III) meso-tetraphenylporphyrin chloride ([Mn(TPP)Cl]) that exhibits labile axial coordination. [Mn(TPP)Cl] shows high chloride transport activity in a bilayer vesicle model with an EC 50 value of 4.42 × 10 -3 mol%. In living cells, [Mn(TPP)Cl] induces rapid chloride influx, and autophagy. The release of Ca 2+ and ATP, as well as the relocation of calreticulin, reveal that [Mn(TPP)Cl] causes immunogenic cell death. Proteomic analysis indicates that [Mn(TPP)Cl] impairs physiological processes, including DNA synthesis and

Aim: Anion/cation symport across cellular membranes may lead to cell apoptosis and be developed as a strategy for new anticancer drug discovery. Methodology: Four aza-crown ether–squaramide conjugates were synthesized and characterized. Their anion recognition, anion/cation symport, cytotoxicity and probable mechanism of action were investigated in details. Conclusion: These conjugates are able to form ion-pairing complexes with chloride anions and facilitate the transmembrane transport of anions via an anion/cation symport process. They can disrupt the cellular homeostasis of chloride anions and sodium cations and induce the basification of acidic organelles in live cells. These conjugates exhibit moderate cytotoxicity toward the tested cancer cells and trigger cell apoptosis by mediating the influx of chloride anions and sodium cations into live cells.

A series of squaramido-tethered bisbenzimidazoles were synthesized and found to exhibit moderate anion transport and cytotoxicity.