Synthesis and biological evaluation of aza-crown ether-squaramide conjugates as anion/cation symporters.

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.

Inhibition of autophagic flux by cyclometalated iridium(iii) complexes through anion transportation.

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.

Highly efficient anion transport mediated by 1,3-bis(benzimidazol-2-yl)benzene derivatives bearing electron-withdrawing substituents.

1,3-Bis(benzimidazol-2-yl)benzene exhibits potent anionophoric activity through a process of anion exchange with a minor level of proton/anion symport. Modification of 1,3-bis(benzimidazol-2-yl)benzene with strong electron-withdrawing substituents, such as trifluoromethyl and nitro groups, leads to up to 789-fold increase in the activity. The benzimidazolyl-NH fragments, the relative position and the number of the benzimidazolyl groups on the central phenyl scaffold play an essential role in the transport.