Diphenylethylenediamine-Based Potent Anionophores: Transmembrane Chloride Ion Transport and Apoptosis Inducing Activities

• Published in: ACS applied materials & interfaces Vol. 10; no. 40; pp. 33803 - 33813
• Main Authors: Akhtar, Nasim, Saha, Abhishek, Kumar, Vishnu, Pradhan, Nirmalya, Panda, Subhankar, Morla, Sudhir, Kumar, Sachin, Manna, Debasis
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.10.2018
• Subjects: apoptosis; Apoptosis - drug effects; binding properties; cell lines; Chloride Channels - metabolism; chlorides; cystic fibrosis; epilepsy; Ethylenediamines - chemical synthesis; Ethylenediamines - chemistry; Ethylenediamines - pharmacology; HeLa Cells; homeostasis; Humans; Ion Transport - drug effects; Ionophores - chemical synthesis; Ionophores - chemistry; Ionophores - pharmacology; ions; materials science; median effective concentration; neoplasm cells; neoplasms; therapeutics; thiourea; transporters; caspase-pathway; membranes; apoptosis; ion carrier; Cl− ion transport
• ISSN: 1944-8244; 1944-8252; 1944-8252
• DOI: 10.1021/acsami.8b06664

Synthetic anion transporters have been recognized as one of the potential therapeutic agents for the treatment of diseases including cystic fibrosis, myotonia, and epilepsy that originate due to the malfunctioning of natural Cl– ion transport systems. Recent studies showed that the synthetic Cl– ion transporters can also disrupt cellular ion-homeostasis and induce apoptosis in cancer cell lines, leading to a revived attention for synthetic Cl– ion transporters. Herein, we report the development of conformationally controlled 1,2-diphenylethylenediamine-based bis­(thiourea) derivatives as a new class of selective Cl– ion carrier. The strong Cl– ion binding properties (K d = 3.87–6.66 mM) of the bis­(thiourea) derivatives of diamine-based compounds correlate well with their transmembrane anion transport activities (EC50 = 2.09–4.15 nM). The transport of Cl– ions via Cl–/NO3 – antiport mechanism was confirmed for the most active molecule. Perturbation of Cl– ion homeostasis by this anion carrier induces cell death by promoting the caspase-mediated intrinsic pathway of apoptosis.