Foldaxanes: Rotaxane-like Architectures from Foldamers.

Mechanically interlocked molecules such as rotaxanes and catenanes contain free-moving components that cannot dissociate and have enabled the investigation and control of various translational and rotational molecular motions. The architecture of pseudo-rotaxanes and of some kinetically labile rotaxanes is comparable to that of rotaxanes but their components are reversibly associated and not irreversibly interlocked. In other words, pseudo-rotaxanes may fall apart. This Account focuses on a peculiar family of rotaxane-like architectures termed foldaxanes.Foldaxanes consist of a helically folded oligomer wound around a rod-like dumbbell-shaped guest. Winding of the helix around the rod thus entails an unwinding-rewinding process that creates a kinetic barrier. It follows that foldaxanes, albeit reversibly assembled, have significant lifetimes and may not fall apart while defined molecular motions are triggered. Foldaxanes based on helically folded aromatic oligoamide hosts and oligo(alkyl carbamate) guests can be designed rationally through the inclusion of complementary binding motifs on the rod and at the inner rim of the helix so that helix length and rod length match. Single helical foldaxanes (bimolecular species) and double helical foldaxanes (trimolecular species) have thus been produced as well as poly[n]foldaxanes, in which several helices bind to long rods with multiple binding stations. When the binding stations differ and are organized in a certain sequence, a complementary sequence of different stacked helices, each matching with their binding station, can be assembled, thus reproducing in an artificial system a sort of translation process.Foldaxane helix handedness may be controlled by stereogenic centers on the rod-like guest. Handedness can also be transmitted from helix to helix in polyfoldaxanes. Foldaxane formation has drastic consequences for the rod properties, including its stiffening and the restriction of the mobility of a macrocycle already interlocked on the rod. Fast translation (without dissociation) of helices along rod-like guests has been demonstrated. Because of the helical nature of the hosts, translation may be accompanied by rotation in various sorts of screw-like motions. The possibility, on longer time scales, for the helix to dissociate from and reassociate to the rod has allowed for the design of complex, kinetically controlled supramolecular pathways of a helix on a rod. Furthermore, the design of helices with a directionality, that is, with two distinct termini, that bind to nonsymmetrical rod-like guests in a defined orientation makes it possible to also control the orientation of molecular motion. Altogether, foldaxanes constitute a distinct and full-of-potential family of rotaxane-like architectures that possess designer structures and allow orchestration of the time scales of various supramolecular events.

Fluorofoldamer-Based Salt- and Proton-Rejecting Artificial Water Channels for Ultrafast Water Transport.

Here, we report on a novel class of fluorofoldamer-based artificial water channels (AWCs) that combines excellent water transport rate and selectivity with structural simplicity and robustness. Produced by a facile one-pot copolymerization reaction under mild conditions, the best-performing channel (AWC 1) is an n-C8H17-decorated foldamer nanotube with an average channel length of 2.8 nm and a pore diameter of 5.2 Å. AWC 1 demonstrates an ultrafast water conduction rate of 1.4 × 1010 H2O/s per channel, outperforming the archetypal biological water channel, aquaporin 1, while excluding salts (i.e., NaCl and KCl) and protons. Unique to this class of channels, the inwardly facing C(sp2)-F atoms being the most electronegative in the periodic table are proposed as being critical to enabling the ultrafast and superselective water transport properties by decreasing the channel's cavity and enhancing the channel wall smoothness via reducing intermolecular forces with water molecules or hydrated ions.

Recent Advances in Bioactive Artificial Ionophores.

Several life-threatening diseases, also known as 'Channelopathies' are linked to irregularities in ion transport proteins. Significant research efforts have fostered the development of artificial transport systems that facilitates to restore the functions of impaired natural transport proteins. Indeed, a few of these artificial ionophores demonstrate the rare combination of transmembrane ion transport and important biological activity, offering early promises of suitability in 'channel replacement therapy'. In this review, structural facets and functions of both cationophores and anionophores are discussed. Ionophores that are toxic to various bacteria and yeast, could be exploited as antimicrobial agent. Nevertheless, few non-toxic ionophores offer the likelihood of treating a wide range of genetic diseases caused by the gene mutations. In addition, their ability to disrupt cellular homeostasis and to alter lysosomal pH endow ionophores as promising candidates for cancer treatment. Overall, critically outlining the advances in artificial ionophores in terms of in vitro ion transport, possible modes of action and biological activities enables us to propose possible future roadmaps in this research area.

Aquafoldmer-Based Aquaporin-like Synthetic Water Channel.

Synthetic water channels were developed with an aim to replace aquaporins for possible uses in water purification, while concurrently retaining aquaporins' ability to conduct highly selective superfast water transport. Among the currently available synthetic water channel systems, none possesses water transport properties that parallel those of aquaporins. In this report, we present the first synthetic water channel system with intriguing aquaproin-like features. Employing a "sticky end"-mediated molecular strategy for constructing abiotic water channels, we demonstrate that a 20% enlargement in angstrom-scale pore volume could effect a remarkable enhancement in macroscopic water transport profile by 15 folds. This gives rise to a powerful synthetic water channel able to transport water at a speed of ∼3 × 109 H2O s-1 channel-1 with a high rejection of NaCl and KCl. This high water permeability, which is about 50% of aquaporin Z's capacity, makes channel 1 the fastest among the existing synthetic water channels with high selectivity.

Polyhydrazide-Based Organic Nanotubes as Efficient and Selective Artificial Iodide Channels.

Reported herein is a series of pore-containing polymeric nanotubes based on a hydrogen-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of about a 6.5 Šdiameter, mediate highly efficient transport of diverse types of anions, rather than cations, across lipid membranes. The reported polymer channel, having an average molecular weight of 18.2 kDa and 3.6 nm in helical height, exhibits the highest anion-transport activities for iodide (EC50 =0.042 µm or 0.028 mol % relative to lipid), whcih is transported 10 times more efficiently than chlorides (EC50 =0.47 µm). Notably, even in cholesterol-rich environment, iodide transport activity remains high with an EC50 of 0.37 µm. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.

Pyridine/Oxadiazole-Based Helical Foldamer Ion Channels with Exceptionally High K+ /Na+ Selectivity.

Protein channels are characterized by high transport selectivity, which is essential for maintaining cellular function. Efforts to reproduce such high selectivity over the past four decades have not been very successful. We report a novel series of aromatic foldamer-based polymeric channels where the backbone is stabilized by differential electrostatic repulsions among heteroatoms helically arrayed along the helical backbone. Nanotubes averaging 2.3 and 2.7 nm in length mediate highly efficient transport of K+ ions as a consequence of hydrophilic electron-rich hollow cavities that are 3 Šin diameter. Exceptionally high K+ and Na+ selectivity values of 16.3 and 12.6, respectively, are achieved.

Molecular Ion Fishers as Highly Active and Exceptionally Selective K+ Transporters.

We report here a unique ion-fishing mechanism as an alternative to conventional carrier or channel mechanisms for mediating highly efficient and exceptionally selective transmembrane K+ flux. The molecular framework, underlying the fishing mechanism and comprising a fishing rod, a fishing line and a fishing bait/hook, is simple yet modularly modifiable. This feature enables rapid construction of a series of molecular ion fishers with distinctively different ion transport patterns. While more efficient ion transports are generally achieved by using 18-crown-6 as the fishing bait/hook, ion transport selectivity (K+/Na+) critically depends on the length of the fishing line, with the most selective MF6-C14 exhibiting exceptionally high selectivity (K+/Na+ = 18) and high activity ( EC50 = 1.1 mol % relative to lipid).

Pore-Forming Monopeptides as Exceptionally Active Anion Channels.

We describe here a unique family of pore-forming anion-transporting peptides possessing a single-amino-acid-derived peptidic backbone that is the shortest among natural and synthetic pore-forming peptides. These monopeptides with built-in H-bonding capacity self-assemble into an H-bonded 1D columnar structure, presenting three types of exteriorly arranged hydrophobic side chains that closely mimic the overall topology of an α-helix. Dynamic interactions among these side chains and membrane lipids proceed in a way likely similar to how α-helix bundle is formed. This subsequently enables oligomerization of these rod-like structures to form ring-shaped ensembles of varying sizes with a pore size of smaller than 1.0 nm in diameter but sufficiently large for transporting anions across the membrane. The intrinsic high modularity in the backbone further allows rapid tuning in side chains for combinatorial optimization of channel's ion-transport activity, culminating in the discovery of an exceptionally active anion-transporting monopeptide 6L10 with an EC50 of 0.10 µM for nitrate anions.

pH-Gated Chloride Transport by a Triazine-Based Tripodal Semicage.

Triazine-based preorganized tripodal receptors are reported as efficient transmembrane Cl- carriers. These receptors were designed based on triazine core and 3,7-diazabicyclo[3.3.1]nonane arms to facilitate preorganized cavity formation. Each bicyclic arm was further functionalized to control protonation and lipophilicity, which are crucial for their efficient anion binding and effective transport through liposomal membranes. The benzyl-substituted receptor was the most effective ion transporter followed by the pentafluorobenzyl-substituted derivative. The nonsubstituted receptor was least active owing to its high polarity. Two active transporters were found to function as mobile carriers for Cl- via an antiport exchange mechanism. Molecular dynamic simulations with the most active receptor show a strong Cl- binding within the cavity by direct and water-mediated H-bonds with its N-H groups.

Trimodal Control of Ion-Transport Activity on Cyclo-oligo-(1→6)-ß-D-glucosamine-Based Artificial Ion-Transport Systems.

Cyclo-oligo-(1→6)-ß-D-glucosamines functionalized with hydrophobic tails are reported as a new class of transmembrane ion-transport system. These macrocycles with hydrophilic cavities were introduced as an alternative to cyclodextrins, which are supramolecular systems with hydrophobic cavities. The transport activities of these glycoconjugates were manipulated by altering the oligomericity of the macrocycles, as well as the length and number of attached tails. Hydrophobic tails of 3 different sizes were synthesized and coupled with each glucosamine scaffold through the amide linkage to obtain 18 derivatives. The ion-transport activity increased from di- to tetrameric glucosamine macrocycles, but decreased further when flexible pentameric glucosamine was introduced. The ion-transport activity also increased with increasing length of attached linkers. For a fixed length of linkers, the transport activity decreased when the number of such tails was reduced. All glycoconjugates displayed a uniform anion-selectivity sequence: Cl(-) >Br(-) >I(-) . From theoretical studies, hydrogen bonding between the macrocycle backbone and the anion bridged through water molecules was observed.

A fluorescent off-on NBD-probe for F(-) sensing: theoretical validation and experimental studies.

The design, synthesis and fluoride sensing ability of a 7-nitro-2,1,3-benzoxadiazole (NBD) based chemodosimeter is reported. Theoretical calculations were used to design a more applicable off-on response, by choosing NBD as the accurate fluorophore. Reaction of the NBD-probe with 300 equivalents of tetrabutyl ammonium fluoride (TBAF) exhibited a response time of 80 minutes and the reaction was selective to F(-) and sensing of the ion was marked by a 110-fold enhancement of green fluorescence. The off-on fluorescence characteristics of the probe enabled its application in live-cell imaging of intracellular F(-) ions.

Diastereoselective construction of syn-α-oxyamines via three-component α-oxyaldehyde-dibenzylamine-alkyne coupling reaction: application in the synthesis of (+)-ß-conhydrine and its analogues.

A Cu(I)-catalyzed α-oxyaldehyde-dibenzylamine-alkyne coupling reaction was delineated for the construction of α-oxyamines with excellent yields and diastereoselectivity. Crystal structure analysis and theoretical calculations were also supportive of the formation of syn-α-oxyamines as the major products. Application of the methodology addresses the synthesis of (+)-ß-conhydrine along with analogs having two different diversity features. A ring size variation allows construction of piperidine and pyrrolidine rings while a variation of side arm functionality is achieved by complete regioselective opening of epoxide by different organocopper ylides (Gilman reagents). A lactam-Cu(I) complexation motif is proposed which allows an intramolecular attack of ylides at the terminal epoxy carbon via the six-membered cyclic transition state. The present work features the synthesis of (+)-ß-conhydrine over eight steps in 26% yield and its seven analogs in 21-28% yields.

Foldamer-based ultrapermeable and highly selective artificial water channels that exclude protons.

The outstanding capacity of aquaporins (AQPs) for mediating highly selective superfast water transport1-7 has inspired recent development of supramolecular monovalent ion-excluding artificial water channels (AWCs). AWC-based bioinspired membranes are proposed for desalination, water purification and other separation applications8-18. While some recent progress has been made in synthesizing AWCs that approach the water permeability and ion selectivity of AQPs, a hallmark feature of AQPs-high water transport while excluding protons-has not been reproduced. We report a class of biomimetic, helically folded pore-forming polymeric foldamers that can serve as long-sought-after highly selective ultrafast water-conducting channels with performance exceeding those of AQPs (1.1 × 1010 water molecules per second for AQP1), with high water-over-monovalent-ion transport selectivity (~108 water molecules over Cl- ion) conferred by the modularly tunable hydrophobicity of the interior pore surface. The best-performing AWC reported here delivers water transport at an exceptionally high rate, namely, 2.5 times that of AQP1, while concurrently rejecting salts (NaCl and KCl) and even protons.

Anion Selective Ion Channel Constructed from a Self-Assembly of Bis(cholate)-Substituted Fumaramide.

The self-assembled ion channel constructed from bis(cholate)-substituted fumaramide is reported. Such ion channel formation was favored by intermolecular hydrogen bonding interactions among fumaramide moieties. Fluorescence kinetics experiments and planar bilayer conductance measurements confirmed the selective chloride transport through the channel. Theoretical calculations were done to confirm the hydrogen bonded self-assembly of fumaramides and chloride recognition within the cavity.

Self-assembly of small-molecule fumaramides allows transmembrane chloride channel formation.

This study reports the formation of self-assembled transmembrane anion channels by small-molecule fumaramides. Such artificial ion channel formation was confirmed by ion transport across liposomes and by planar bilayer conductance measurements. The geometry-optimized model of the channel and Cl- ion selectivity within the channel lumen was also illustrated.

A halogen bond-mediated highly active artificial chloride channel with high anticancer activity.

Chloride-selective transmembrane carriers or channels might have possible uses in treating channelopathies or cancers. While chloride carriers have been extensively investigated, the corresponding chloride channels have remained limitedly studied. Moreover, all hitherto reported channel systems lack clearly definable and readily modifiable positions in their structures for the reliable construction and combinatorial optimization of their ion transport properties. As a result, the existing channels are limited by their large molecular weight, weak activity or low anion selectivity. In this report, we describe a readily accessible and robust monopeptide-based scaffold for the reliable construction of halogen bond-mediated artificial anion channels via directional assembly of electron-deficient iodine atoms, which create a transmembrane pathway for facilitating anion transport. The high intrinsic modularity of the backbone of the scaffold, which enables the rapid and combinatorial optimization of the transport activity and selectivity of channels, effectively delivers a highly active chloride channel A10. Such high activity in chloride transport subsequently leads to an excellent IC50 value of 20 µM toward inhibiting the growth of human breast cancer cells (BT-474), an anticancer activity that is even higher than that of the well-known anticancer agent cisplatin.

Bis(sulfonamide) transmembrane carriers allow pH-gated inversion of ion selectivity.

Bis(sulfonamide) based synthetic carriers are reported for inversion of ion selectivity upon deviation of pH within a narrow window. A liposomal membrane potential is also generated when potassium ions are passively transported by these carriers.

One-Pot Synthesis and Transmembrane Chloride Transport Properties of C3-Symmetric Benzoxazine Urea.

One-pot synthesis of a C3-symmetric benzoxazine-based tris-urea compound is discussed. 1H NMR titrations indicate a stronger Cl- binding compared that of Br- and I- by the receptor. Effective Cl- transport across liposomal membranes via a Cl-/X- antiport mechanism is confirmed. Theoretical calculation suggests that a few water molecules with N-H, C═O, and the aromatic ring of the receptor create a H-bonded polar cavity where a Cl- is recognized by O-H···Cl- interactions from five bridged water molecules.

A cascade reaction based fluorescent probe for rapid and selective fluoride ion detection.

A cascade reaction-based colorimetric and fluorescent probe for selective fluoride ion detection is reported. The probe displays a fast response (t1/2 = 2.41 min) and 550-fold fluorescence enhancement during sensing of fluoride ions. Application of the probe in live cell imaging is demonstrated.

Cyclo-oligo-(1 → 6)-ß-D-glucosamine based artificial channels for tunable transmembrane ion transport.

Unimolecular ion channels were designed by functionalization of a new type of cyclic oligosaccharides, cyclo-oligo-(1 → 6)-ß-d-glucosamines, with pentabutylene glycol chains. Their ion transporting activity was tuned by varying oligomericity. A halide selectivity sequence, Cl(-) > Br(-) > I(-) was observed.