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

Abstract

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 = 3.87-6.66 mM) of the bis(thiourea) derivatives of diamine-based compounds correlate well with their transmembrane anion transport activities (EC = 2.09-4.15 nM). The transport of Cl ions via Cl/NO 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.

Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization

“…LUVs were prepared following a standard literature method. 66 20 mM DOPC/DOPG -LUVs containing 100 mM NaCl in the intravesicular and 100 mM NaNO 3 in the extravesicular space were prepared by mixing DOPC and DOPG in molar ratio of 7 : 3 from chloroform stocks in a clean and dry round bottom flask. A thin film of DOPC/DOPG was obtained by purging nitrogen gas for 30 min over the chloroform solution.…”

“…68,69 The experimental setup was further validated by a selective anionophore prodigiosine (Fig. S12 †), 66 and a membrane disrupting agent Triton-X (Fig. S13 †).…”

Recent Advances in Bioactive Artificial Ionophores

“…These molecules carried anions with significant transport efficiency versus other biologically relevant cations and the antiport mechanism could be identified (Figure 12D). [47] Here, anion carriers induced perturbation of Cl À ion homeostasis and led to the death of HeLa cell line by promoting the caspase-mediated intrinsic pathway of apoptosis. Last year, Rawling et al reported a series of fatty acid substituted urea-based (also termed as, aryl-urea) anion transporters (45 a-45 d) and their function as mitochondrial uncouplers.…”

Supramolecular methods: the 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) transport assay

“…A literature search shows that egg yolk phosphatidylcholine (EYPC) and 2-oleoyl-1-palmitoyl-sn-glycero-3phosphocholine (POPC, Figure 5) are the most commonly used lipids; however, 1palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2oleoyl-sn-glycero-3-phosphoglycerol (POPG) have also been employed. For instance, Matile's, [22][23][24][25][26][27] Talukdar's, [28][29][30][31][32] and Ballester's 22,33 research groups have used EYPC from Avanti Polar Lipids, while Chen [34][35][36][37][38] and Manna 39,40 have also used EYPC but purchased from Sigma-Aldrich. On the other hand, the Gale, 15,18,21,[41][42][43][44] and Quesada 45, As indicated before, when it comes to choosing the appropriate lipid to conduct transport assays, the decision should be made by considering, among other factors, the biological membranes to be mimicked.…”

“…16,21 Finally, it is important to note that sometimes a mixture of lipid and cholesterol has been prepared to carry out transport experiments due to the contribution of the latter to the stabilisation of the vesicles' membrane. 34,39,40,46 Their proportions may vary, but Quesada's group uses a 7:3 POPC:cholesterol mixture with good results.…”