Anion-Selective Cholesterol Decorated Macrocyclic Transmembrane Ion Carriers

Abstract

Anion transporters play a vital role in cellular processes and their dysregulation leads to a range of diseases such as cystic fibrosis, Bartter's syndrome and epilepsy. Synthetic chloride transporters are known to induce apoptosis in cancer cell lines. Herein, we report triamide macrocycles that are easily synthesized and externally functionalized by pendant membrane-permeable groups. Among a variety of chains appended onto the macrocycle scaffold, cholesterol is found to be the best with an EC value of 0.44 μM. The macrocycle is highly anion-selective and transports ions via an OH/X antiport mechanism. The macrocycle is an interesting scaffold for ion-transport as it is able to discriminate between various anions and shows a preference for SCN and Cl. Such anion-selective transporters are highly attractive model systems to study ion-transport mechanisms and could potentially be of high therapeutic value.

Heavy Pnictogenium Cations as Transmembrane Anion Transporters in Vesicles and Erythrocytes

“…46 It is also possible that the more lipophilic cations can aggregate in the membrane or even partly precipitate from solution, thus lowering anion transport. [47][48][49] A B C To verify our interpretation that these cations behave as mobile fluoride ion carriers, we tested the transport properties of [3] + and [7] + by using DPPC-based vesicles (DPPC = 1,2-dipalmitoyl-sn-glycero-3-phosphtidylcholine) (Figure 6C). This phospholipid is known to form temperature sensitive bilayers that undergo a phase transition between a gel and a liquid at 41 C. 48,49 It has been previously suggested that channel-type transporters are less affected by this phase transition.…”

“…[47][48][49] A B C To verify our interpretation that these cations behave as mobile fluoride ion carriers, we tested the transport properties of [3] + and [7] + by using DPPC-based vesicles (DPPC = 1,2-dipalmitoyl-sn-glycero-3-phosphtidylcholine) (Figure 6C). This phospholipid is known to form temperature sensitive bilayers that undergo a phase transition between a gel and a liquid at 41 C. 48,49 It has been previously suggested that channel-type transporters are less affected by this phase transition. 50 However, in the case of [3] + and [7] + , we observed a drastic decrease in transport when the temperature of the assay was lowered from 45 C to 25 C, indicating that transport is significantly affected by the fluidity of the bilayer.…”

Ligand Induced CuII Transport Restricts Cancer and Mycobacterial Growth: Towards a Plug‐and‐Select Ion Channel Scaffold

“…[5] A plug-and-select scaffold, wherein the ion selectivity can be precisely tuned by changing the ion-binding motif is highly desirable for therapeutic applications. Our group has developed a variety of acyclic [6] and macrocyclic [7] scaffolds for transporting cation, and anions, respectively. Our studies with the acyclic scaffolds [8] have led us to propose a simple alanine derived tripeptide scaffold with a selectivity inducing unit at the C terminus as a potential universal scaffold (Figure 1A).…”

Imidazolinium‐based Multiblock Amphiphile as Transmembrane Anion Transporter

“…Ion channels form pores for ions to pass through the membranes, whereas mobile carriers bind with anions and diffuse across the membranes. Therefore, ion transport efficiency of mobile carriers strongly depends on the membrane fluidity since diffusion is restricted in the membranes with low fluidity, while ion channels are not significantly affected, as transmembrane diffusion is less important [25–27] . Thus influence of the membrane fluidity was investigated using 1,2‐dipalmitoyl‐ sn ‐glycero‐3‐phosphocholine (DPPC) instead of DOPC for HPTS assay.…”

“…Therefore, ion transport efficiency of mobile carriers strongly depends on the membrane fluidity since diffusion is restricted in the membranes with low fluidity, while ion channels are not significantly affected, as transmembrane diffusion is less important. [25][26][27] Thus influence of the membrane fluidity was investigated using 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) instead of DOPC for HPTS assay. DPPC adopts highly fluid liquid phase above the phase transition temperature (T m = 41°C), and much less fluid gel phase below T m .…”