An Exceptionally Active and Highly Selective Perchlorate Transporter Containing a Trimesic Amide Scaffold.

We report here a series of alkyl group-modified trimesic amide molecules (TAs) with excellent anion transport activities. Among them, TA6, with the highest ion transport activity and excellent selectivity, efficiently transports anions across the membrane in the order of ClO4- > I- > NO3- > Br- > Cl-, with an EC50 value as low as 17.6 nM (0.022 mol% relative to lipid molecules) for ClO4-, which outperforms other anions by 5- to 22-folds and manifests as the best perchlorate transporter ever reported.

Artificial transmembrane potassium transporters: designs, functions, mechanisms and applications.

Potassium channels represent the most prevalent class of ion channels, exerting regulatory control over numerous vital biological processes, including muscle contraction, neurotransmitter release, cell proliferation, and apoptosis. The seamless integration of astonishing functions into a sophisticated structure, as seen in these protein channels, inspires the chemical community to develop artificial versions, gearing toward simplifying their structure while replicating their key functions. In particular, over the past ten years or so, a number of elegant artificial potassium transporters have emerged, demonstrating high selectivity, high transport efficiency or unprecedented transport mechanisms. In this review, we will provide a detailed exposition of these artificial potassium transporters that are derived from a single molecular backbone or self-assembled from multiple components, with their respective structural designs, channel functions, transport mechanisms and biomedical applications thoroughly reviewed.

Sulfur-Containing Foldamer-Based Artificial Lithium Channels.

Unlike many other biologically relevant ions (Na+ , K+ , Ca2+ , Cl- , etc) and protons, whose cellular concentrations are closely regulated by highly selective channel proteins, Li+ ion is unusual in that its concentration is well tolerated over many orders of magnitude and that no lithium-specific channel proteins have so far been identified. While one naturally evolved primary pathway for Li+ ions to traverse across the cell membrane is through sodium channels by competing with Na+ ions, highly sought-after artificial lithium-transporting channels remain a major challenge to develop. Here we show that sulfur-containing organic nanotubes derived from intramolecularly H-bonded helically folded aromatic foldamers of 3.6 Šin hollow cavity diameter could facilitate highly selective and efficient transmembrane transport of Li+ ions, with high transport selectivity factors of 15.3 and 19.9 over Na+ and K+ ions, respectively.

Effect of the Second Phases on Composite Spinning-Extrusion Forming and Mechanical Properties of Al-Cu-Li Alloy.

The aim of this work is to investigate the effect of different second phases on the composite spinning-extrusion forming and mechanical properties of Al-Cu-Li alloy. With that purpose, four kinds of second phases blanks were controlled using preheating treatment, composite spinning-extrusion forming and mechanical properties test. Then, the correlation between the second phases and mechanical properties was further analyzed using electron backscattered diffraction and transmission electron microscopy. The results indicated that different second phases of Al-Cu-Li alloy can be regulated via reasonable preheating treatment. In addition, different second phases in the blank have various influences on composite spinning-extrusion forming, microstructure and mechanical properties of cylindrical parts. Dissolving the coarse second phases particles and precipitating the Al3Zr dispersoid in the blank can effectively improve the composite spinning-extrusion forming, inhibit the abnormal growth of recrystallized grains, and significantly enhance the mechanical properties of cylindrical parts with ribs. After regulation, the average grain size of the cylindrical parts is refined from about 90 µm to about 45 µm, and the average diameter of T1 phase is refined from 107 nm to 77 nm. In addition, the ultimate tensile strength, yield strength and elongation of cylindrical parts are increased from 555 MPa to 588 MPa, 530 MPa to 564 MPa, and 9.1% to 11%, respectively.

A K+-selective channel with a record-high K+/Na+ selectivity of 20.1.

For compounds each containing a phenylalanine moiety with its two ends amidated to have a 15-crown-5 unit and an alkyl chain, a simple tuning of the alkyl chain length delivered a K+-selective channel with a record-high K+/Na+ selectivity of 20.1.

Guanidinium-Perfunctionalized Polyhedral Oligomeric Silsesquioxanes as Highly Potent Antimicrobials against Planktonic Microbes, Biofilms, and Coronavirus.

Supramolecules have been drawing increasing attention recently in addressing healthcare challenges caused by infectious pathogens. We herein report a novel class of guanidinium-perfunctionalized polyhedral oligomeric silsesquioxane (Gua-POSS) supramolecules with highly potent antimicrobial activities. The modular structure of Gua-POSS Tm-Cn consists of an inorganic T10 or T8 core (m = 10 or 8), flexible linear linkers of varying lengths (n = 1 or 3), and peripherally aligned cationic guanidinium groups as the membrane-binding units. Such Gua-POSS supramolecules with spherically arrayed guanidinium cations display high antimicrobial potency against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria, as well as fungus (Candida albicans), with the best showing excellently low minimal inhibitory concentrations (MICs) of 1.7-6.8 µM in media, yet with negligible hemolytic activity and low in vitro cytotoxicity to mammalian cells. More significantly, they can inhibit biofilm formation at around their MICs and near-completely break down preestablished difficult-to-break biofilms at 250 µg mL-1 (∼50 µM). Their strong antiviral efficacy was also experimentally demonstrated against the enveloped murine hepatitis coronavirus as a surrogate of the SARS-CoV species. Overall, this study provides a new design approach to novel classes of sphere-shaped organic-inorganic hybrid supramolecular materials, especially for potent antimicrobial, anti-biofilm, and antiviral applications.

Cholesterol-stabilized membrane-active nanopores with anticancer activities.

Cholesterol-enhanced pore formation is one evolutionary means cholesterol-free bacterial cells utilize to specifically target cholesterol-rich eukaryotic cells, thus escaping the toxicity these membrane-lytic pores might have brought onto themselves. Here, we present a class of artificial cholesterol-dependent nanopores, manifesting nanopore formation sensitivity, up-regulated by cholesterol of up to 50 mol% (relative to the lipid molecules). The high modularity in the amphiphilic molecular backbone enables a facile tuning of pore size and consequently channel activity. Possessing a nano-sized cavity of ~ 1.6 nm in diameter, our most active channel Ch-C1 can transport nanometer-sized molecules as large as 5(6)-carboxyfluorescein and display potent anticancer activity (IC50 = 3.8 µM) toward human hepatocellular carcinomas, with high selectivity index values of 12.5 and >130 against normal human liver and kidney cells, respectively.

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.

Directionally Aligned Crown Ethers as Superactive Organocatalysts for Transition-metal Ion-free Arylation of Unactivated Arenes.

When one-dimensionally aligned to the same side, multiple non-covalently associated crown ether groups could act as a whole to yield a higher catalytic activity than an individual poorly active crown ether group, delivering the lowest catalyst loading of 1-2 mol % among all hitherto known organocatalysts for catalyzing direct arylation of unactivated arenes with haloarenes.

Hybrid Pyridine-Pyridone Foldamer Channels as M2-Like Artificial Proton Channels.

Currently, completely abiotic channel systems that concurrently reproduce the high selectivity and high permeation rate of natural protein channels are rare. Here, we provide one such biomimetic channel system, i.e., a novel family of helically folded hybrid amide foldamers that can serve as powerful artificial proton channels to mimic key transport features of the exceptionally selective Matrix-2 (M2) proton channels. Possessing an angstrom-scale tubular pore 3 Šin diameter, these low water permeability artificial channels transport protons at a rate 1.22 and 11 times as fast as gramicidin A and M2 channels, respectively, with exceptionally high selectivity factors of 167.6, 122.7, and 81.5 over Cl- , Na+ , and K+ ions. Based on the experimental and computational findings, we propose a novel proton transport mechanism where a proton may create a channel-spanning water chain from two or more short water chains to facilitate its own transmembrane flux via the Grotthuss mechanism.

Membrane-Active Molecular Machines.

Both biological and artificial membrane transporters mediate passive transmembrane ion flux predominantly via either channel or carrier mechanisms, tightly regulating the transport of materials entering and exiting the cell. One early elegant example unclassifiable as carriers or channels was reported by Smith who derivatized a phospholipid molecule into an anion transporter, facilitating membrane transport via a two-station relay mechanism (Smith et al. J. Am. Chem. Soc. 2008, 130, 17274-17275). Our journey toward blurring or even breaking the boundaries defined by the carrier and channel mechanisms starts in January of 2018 when seeing a child swinging on the swing at the playground park. Since then, I have been wondering whether we could build a nanoscale-sized molecular swing able to perform the swing function at the molecular level to induce transmembrane ion flux. Such research journey culminates in several membrane-active artificial molecular machines, including molecular swings, ion fishers, ion swimmers, rotors, tetrapuses and dodecapuses that permeabilize the membrane via swinging, ion-fishing, swimming, rotating, or swing-relaying actions, respectively. Except for molecular ion swimmers, these unconventional membrane transporters in their most stable states readily span across the entire membrane in a way akin to channels. With built-in flexible arms that can swing or bend in the dynamic membrane environment, they transport ions via constantly changing ion permeation pathways that are more defined than carriers but less defined than channels. Applying the same benzo-crown ether groups as the sole ion-binding and -transporting units, these transporters however differ immensely in ion transport property. While the maximal K+ transport activity is achieved by the molecular swing also termed "motional channel" that displays an EC50 value of 0.021 mol % relative to lipid and transports K+ ions at rate 27% faster than gramicidin A, the highest K+/Na+ selectivity of 18.3 is attained by the molecular ion fisher, with the highest Na+/K+ selectivity of 13.7 by the molecular dodecapus. Having EC50 values of 0.49-1.60 mol % and K+/Na+ values of 1.1-6.3, molecular rotors and tetrapuses are found to be generally active but weakly to moderately K+-selective. For molecular ion swimmers that contain 10 to 14 carbon atom alkyl linkers, they all turn out to be highly active (EC50 = 0.18-0.41 mol %) and highly selective (RK+/RNa+ = 7.0-9.5) transporters. Of special note are crown ether-appended molecular dodecapuses that establish the C60-fullerene core as an excellent platform to allow for a direct translation of solution binding affinity to transmembrane ion transport selectivity, providing a de novo basis for rationally designing artificial ion transporters with high transport selectivity. Considering remarkable cytotoxic activities displayed by molecular swings and ion swimmers, the varied types of existing and emerging unconventional membrane transporters with enhanced activities and selectivities eventually might lead to medical benefits in the future.

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.

Crystal Packing-Guided Construction of Hetero-Oligomeric Peptidic Ensembles as Synthetic 3-in-1 Transporters.

Strategies to generate heteromeric peptidic ensembles via a social self-sorting process are limited. Herein, we report a crystal packing-inspired social self-sorting strategy broadly applicable to diverse types of H-bonded peptidic frameworks. Specifically, a crystal structure of H-bonded alkyl chain-appended monopeptides reveals an inter-chain separation distance of 4.8 Šdictated by the H-bonded amide groups, which is larger than 4.1 Šseparation distance desired by the tightly packed straight alkyl chains. This incompatibility results in loosely packed alkyl chains, prompting us to investigate and validate the feasibility of applying bulky tert-butyl groups, modified with an anion-binding group, to alternatively interpenetrate the straight alkyl chains, modified with a crown ether group. Structurally, this social self-sorting approach generates highly stable hetero-oligomeric ensembles, having alternated anion- and cation-binding units vertically aligned to the same side. Functionally, these hetero-oligomeric ensembles promote transmembrane transport of cations, anions and more interestingly zwitterionic species such as amino acids.

Small Molecule-Based Highly Active and Selective K+ Transporters with Potent Anticancer Activities.

We report here a novel class of cation transporters with extreme simplicity, opening a whole new dimension of scientific research for finding small molecule-based cation transporters for therapeutic applications. Comprising three modular components (a headgroup, a flexible alkyl chain-derived body, and a crown ether-derived foot for ion binding), these transporters efficiently (EC50 = 0.18-0.41 mol % relative to lipid) and selectively (K+/Na+ selectivity = 7.0-9.5) move K+ ions across the membrane. Importantly, the most active (EC50 = 0.18-0.22 mol %) and highly selective series of transporters A12, B12, and C12 concurrently possess potent anticancer activities with IC50 values as low as 4.35 ± 0.91 and 6.00 ± 0.13 µM toward HeLa and PC3 cells, respectively. Notably, a mere replacement of the 18-crown-6 unit in the structure with 12-crown-4 or 15-crown-5 units completely annihilates the cation-transporting ability.

Buckyball-Based Spherical Display of Crown Ethers for De Novo Custom Design of Ion Transport Selectivity.

Searching for membrane-active synthetic analogues that are structurally simple yet functionally comparable to natural channel proteins has been of central research interest in the past four decades, yet custom design of the ion transport selectivity still remains a grand challenge. Here we report on a suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity to be custom designable. The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, intriguingly revealed that their transport selectivity well resembles the intrinsic ion binding affinity of the respective benzo-crown units present, making custom design of the transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, all are Li+-selective in transmembrane ion transport, with the most active MB4-C10 exhibiting an EC50(Li+) value of 0.13 µM (corresponding to 0.13 mol % of the lipid present) while excluding all other monovalent alkali-metal ions. Likewise, the most Na+ selective MB5-C8 and K+ selective MB6-C8 demonstrate high Na+/K+ and K+/Na+ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb+ and Cs+ ions, the most active MB7-C8 displays exceptionally high transport efficiencies, with an EC50(Rb+) value of 105 nM (0.11 mol %) and an EC50(Cs+) value of 77 nM (0.079 mol %).

Macrocyclic Pyridone Pentamers for Highly Selective High-Capacity Removal of Caesium Ions from Radioactive High-Salinity Waste.

We report here that macrocyclic H-bonded pyridone pentamers, containing five properly and convergently spaced electron-rich O-atoms that decorate a rigid cavity of 2.85 Šacross, exhibit an extraordinarily high yet pH-independent capacity and selectivity in Cs+ removal. In particular, with [host]=240 µM and [Cs+ ]=15 µM, a single extraction efficiently removes more than 91% of Cs+ ions from artificial sea water, containing various competitive metal ions at a total concentration of 0.68 M ([total Mn+ ]/[Cs+ ]=4.5×104 ]). To our best knowledge, these pyridone pentamers represent the best small organic molecule-based extractants that target Cs+ ions.

Monopeptide-Based Powder Gelators for Instant Phase-Selective Gelation of Aprotic Aromatics and for Toxic Dye Removal.

Through a combinatorial screening of 35 possible phase-selective monopeptide-based organogelators readily made at low cost, we identified five of them with high gelling ability toward aprotic aromatic solvents in the powder form. The best of them (Fmoc-V-6) is able to instantly and phase-selectively gel benzene, toluene, and xylenes in the presence of water at room temperature at a gelator loading of 6% w/v. This enables the gelled aromatics to be separated by filtration and both aromatics and the gelling material to be recycled by distillation. We also identified Fmoc-I-16 as the best gelator for benzyl alcohol, and the corresponding organogel efficiently removes toxic dye molecules by 82-99% from their highly concentrated aqueous solutions. These efficient removals of toxic organic solvents and dyes from water suggest their promising applications in remediating contaminated water resources.

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.

Polypyridine-Based Helical Amide Foldamer Channels: Rapid Transport of Water and Protons with High Ion Rejection.

Synthetic strategies that enable rapid construction of covalent organic nanotubes with an angstrom-scale tubular pore remain scarcely reported. Reported here is a remarkably simple and mild one-pot polymerization protocol, employing POCl3 as the polymerization agent. This protocol efficiently generates polypyridine amide foldamer-based covalent organic nanotubes with a 2.8 nm length at a yield of 50 %. Trapping single-file water chains in the 2.8 Štubular cavity, rich in hydrogen-bond donors and acceptors, these tubular polypyridine ensembles rapidly and selectively transport water at a rate of 1.6×109  H2 O⋅S-1 ⋅channel-1 and protons at a speed as fast as gramicidin A, with a high rejection of ions.