Beyond Single-Cycle Autonomous Molecular Machines: Light-Powered Shuttling in a Multi-Cycle Reaction Network.

Biomolecular machines autonomously convert energy into functions, driving systems away from thermodynamic equilibrium. This energy conversion is achieved by leveraging complex, kinetically asymmetric chemical reaction networks that are challenging to characterize precisely. In contrast, all known synthetic molecular systems in which kinetic asymmetry has been quantified are well described by simple single-cycle networks. Here, we report on a unique light-driven [2]rotaxane that enables the autonomous operation of a synthetic molecular machine with a multi-cycle chemical reaction network. Unlike all prior systems, the present one exploits a photoactive macrocycle, which features a different photoreactivity depending on the binding sites at which it resides. Furthermore, E to Z isomerization reverses the relative affinity of the macrocycle for two binding sites on the axle, resulting in a multi-cycle network. Building on the most recent theoretical advancements, this work quantifies kinetic asymmetry in a multi-cycle network for the first time. Our findings represent the simplest rotaxane capable of autonomous shuttling developed so far and offer a general strategy to generate and quantify kinetic asymmetry beyond single-cycle systems.

Imidazolium-decorated Bis-cyanostilbene Macrocycle: An Effect Fluorescence Sensor for Pesticide Starane.

Fluorescence sensors for complicated molecules such as pesticides were paid much attention lately due to the merits of simple operation, high sensitivity and selectivity, and in-situ detection. In this work, a novel fluorescent sensor for pesticide starane was prepared based on imidazolium-decorated bis-cyanostilbene macrocycle (IBM). IBM exhibited the obvious "turn-on" fluorescence change from dark blue-green to bright blue after sensing starane with the high sensing selectivity among 28 kinds of guests. The detecting limitation was as low as 0.011 µM, which was the lowest one in literatures. The sensing mechanism was confirmed as that starane was located in cavity of IBM based on the molecular interaction of multiple hydrogen bonds, π-π stacking and hydrophobic interaction. The application experiments suggested that starane was examined well on test paper with good selectivity and was quantitatively detected in water samples, implying the good real-time and in-situ application potential for IBM on sensing starane in real environment and daily life.

Columnar Organization of Nonalternant Fluorinated Dehydrobenzannulenes.

Two new partially fluorinated dehydrobenzannulenes have been prepared by inter- and intramolecular oxidative homocoupling of diyne precursors. These systems contain fluorinated and nonfluorinated arene rings in a non-alternant arrangement. Both macrocycles are roughly planar and organize into extended columns in the solid state. The assembly of these columns is mediated by the combination of dispersion interactions, slipped [π···π] stacking interactions of the perfluorinated rings with each other, and their association with the nonfluorinated rings in the molecules of the neighboring macrocycles. These results suggest that partial fluorination of dehydrobenzannulenes can serve as a versatile motif for their assembly into columnar superstructures.

Aqueous colloid flow batteries with nano Prussian blue.

Flow battery is a safe and scalable energy storage technology in effectively utilizing clean power and mitigating carbon emissions from fossil fuel consumption. In the present work, we demonstrate an aqueous colloid flow battery (ACFB) with well-dispersed colloids based on nano-sized Prussian blue (PB) cubes, aiming at expanding the chosen area of various nano redox materials and lowering the cost of chemicals. Taking advantage of the two redox pairs of PB, the developed all-PB cell employing a low-cost dialysis membrane with the synthesized PB on both sides displays an open-circuit voltage (OCV) of 0.74 V. Moreover, when paired with an organic tetra pyridine macrocycle the cell with PB as positive electrolyte exhibits an OCV of 1.33 V and a capacity fade rate of 0.039 %/cycle (0.8 %/day). Redox-active colloids exhibit enduring physicochemical stability, with no evident structural or morphological changes after extensive cycling, highlighting their potential for cost-effective and reliable ACFB energy storage.

Preparation and evaluation of a 1,1'-bi-2-naphthol-based chiral macrocycle bonded silica chiral stationary phase for high performance liquid chromatography.

Macrocycles play vital roles in supramolecular chemistry and chromatography. 1,1'-Bi-2-naphthol (BINOL)-based chiral polyimine macrocycles are an emerging class of chiral macrocycles that can be constructed by one-step aldehyde-amine condensation of BINOL derivatives with other building blocks. These macrocycles exhibit good characteristics, such as facile preparation, rigid cyclic structures, multiple chiral centers, and defined molecular cavities, that make them good candidates as new chiral recognition materials for chromatographic enantioseparations. In this study, a BINOL-based [2+2] chiral polyimine macrocycle was synthesized by one-step condensation of enantiopure (S)-2,2'-dihydroxy-[1,1'-binaphthalene]-3,3'-dicarboxaldehyde with (1R,2R)-1,2-diaminocyclohexane. The product was modified with 5-bromo-1-pentene and then attached to thiolated silica using click chemistry to construct a new chiral stationary phase (CSP). The enantioselectivity of the new CSP was explored by separating various racemates under normal phase (NP) and reversed phase (RP) high performance liquid chromatography (HPLC). Thirteen racemates and eight racemates were enantioseparated under the two separation modes, respectively, including chiral alcohols, phenols, esters, ketones, amines, and organic acids. Among them, nine racemates achieved baseline separation under NP-HPLC and seven racemates achieved baseline separation under RP-HPLC. High resolution separation was observed with benzoin (Rs = 5.10), epinephrine (Rs = 4.98), 3-benzyloxy-1,2-propanediol (Rs = 4.42), and 4,4'-dimethylbenzoin (Rs = 4.52) in NP-HPLC, and with 4-methylbenzhydrol (Rs = 4.72), benzoin ethyl ether (Rs = 3.79), 1-phenyl-1-pentanol (Rs = 3.68), and 1-(3-bromophenyl)ethanol (Rs = 3.60) in RP-HPLC. Interestingly, the CSP complemented Chiralcel OD-H, Chiralpak AD-H, and CYCLOBOND I 2000 RSP columns for resolution of these test racemates, separating several racemic compounds that could not be well separated by the three commercially available columns. The influences of injected sample amount on separation were also evaluated. It was found that the column exhibited excellent stability and reproducibility after hundreds of injections, and the relative standard deviations (n = 5) of the retention time and resolution were less than 0.49% and 0.69%, respectively. This study indicates that the BINOL-based chiral macrocycle has great potential for HPLC enantioseparation.

La percepción de cansancio en decatlonistas, en diferentes etapas del macrociclo de entrenamiento

El control del comportamiento de la percepción de cansancio a lo largo del macrociclo de entrenamiento en decatlonistas constituye un indicador para la valoración del proceso de asimilación psicofísica del trabajo realizado acorde a la etapa del macrociclo de entrenamiento por la que transita el atleta. Sin embargo, el insuficiente conocimiento sobre el tema en el decatlón ha limitado el uso de este indicador en el control psicológico de la preparación en este deporte. El objetivo de este trabajo consiste en determinar el comportamiento de la percepción de cansancio en las diferentes etapas del macrociclo de entrenamiento, en decatlonistas de la selección nacional de atletismo de Cuba. Es un estudio descriptivo, en el que se aplica la entrevista para un diagnóstico inicial y la Escala de Borg (modificada), para la medición de la percepción de cansancio. Fueron realizadas 416 mediciones de la percepción de cansancio, durante las etapas de preparación física, general, especial y competitiva. Como principales resultados, la percepción de cansancio aumentó en la etapa de preparación física general en una magnitud de 3.48, en la etapa especial en un 3.43 y en la competitiva en un 2.56. La percepción de cansancio en los decatlonistas estudiados aumentó, significativamente, posterior a las cargas de entrenamiento en cada una de las etapas estudiadas y disminuyó, a medida que avanzó el macrociclo de entrenamiento. La etapa competitiva resultó ser aquella de menor cansancio percibido pre- y poscarga, y la de preparación física general, la de mayor aumento en este proceso.

O controle do comportamento da percepção da fadiga ao longo do macrociclo de treinamento em decatletas constitui um indicador para a avaliação do processo de assimilação psicofísica do trabalho realizado de acordo com a etapa do macrociclo de treinamento pela qual o atleta passa. Contudo, o conhecimento insuficiente sobre o tema no decatlo tem limitado a utilização deste indicador no controle psicológico da preparação neste esporte. O objetivo deste trabalho é determinar o comportamento da percepção da fadiga nas diferentes etapas do macrociclo de treinamento, em decatlonistas da seleção cubana de atletismo. Trata-se de um estudo descritivo, no qual é aplicada a entrevista para diagnóstico inicial e a Escala de Borg (modificada) para mensurar a percepção de fadiga. Foram realizadas 416 medidas de percepção de fadiga durante as etapas de preparação física, geral, especial e competitiva. Como principais resultados, a percepção de fadiga aumentou na etapa de preparação física geral em uma magnitude de 3,48, na etapa especial em 3,43 e na etapa competitiva em 2,56. A percepção de fadiga no decatleta estudado aumentou significativamente após as cargas de treinamento em cada uma das etapas estudadas e diminuiu à medida que o macrociclo de treinamento avançava. A etapa competitiva acabou sendo a que apresentou menor fadiga percebida pré e pós-carga, e a etapa de preparação física geral, a que apresentou maior aumento nesse processo.

The control of the behavior of the perception of tiredness throughout the training macrocycle in decathletes constitutes an indicator for the assessment of the process of psychophysical assimilation of the work carried out according to the stage of the training macrocycle through which the athlete goes. However, insufficient knowledge on the subject in the decathlon has limited the use of this indicator in the psychological control of preparation in this sport. The objective of this work is to determine the behavior of the perception of tiredness in the different stages of the training macrocycle, in tiredness of the Cuban national athletics team. It is a descriptive study, in which the interview is applied for an initial diagnosis and the Borg Scale (modified) to measure the perception of tiredness. 416 measurements of the perception of tiredness were carried out during the stages of general, special and competitive physical preparation. As the main results, the perception of tiredness increased in the general physical preparation stage by a magnitude of 3.48, in the special stage by 3.43 and in the competitive stage by 2.56. The perception of tiredness in the decathletes studied increased significantly after the training loads in each of the stages studied and decreased as the training macrocycle progressed. The competitive stage turned out to be the one with the least perceived pre- and post-load tiredness, and the general physical preparation stage was the one with the greatest increase in this process.

Probing the Topological Effects on Stability Enhancement and Therapeutic Performance of Protein Bioconjugates: Tadpole, Macrocycle versus Figure-of-Eight.

Chemical topology provides a unique dimension for making therapeutic protein bioconjugates with native structure and intact function, yet the effects of topology remain elusive. Herein, the design, synthesis, and characterization of therapeutic protein bioconjugates in three topologies (i.e., tadpole, macrocycle, and figure-of-eight), are reported. The interferon α2b (IFN) and albumin binding domain (ABD) are selected as the model proteins for bioconjugation and proof-of-concept. The biosynthesis of these topological isoforms is accomplished via direct expression in cells using SpyTag-SpyCatcher chemistry and/or split-intein-mediated ligation for topology diversification. The corresponding topologies are proven with combined techniques of LC-MS, SDS-PAGE, and controlled proteolytic digestion. While the properties of these topological isoforms are similar in most cases, the figure-of-eight-shaped bioconjugate, f8-IFN-ABD, exhibits the best thermal stability and anti-aggregation properties along with prolonged half-life and enhanced tumor retention relative to the tadpole-shaped control, tadp-IFN-ABD, and the macrocyclic control, c-IFN-ABD, showcasing considerable topological effects. The work expands the topological diversity of proteins and demonstrates the potential advantages of leveraging chemical topology for functional benefits beyond multi-function integration in protein therapeutics.

Facile synthesis of a new chiral polyimine macrocycle and its application for enantioseparation in high-performance liquid chromatography.

Macrocyclic compounds such as crown ethers and cyclodextrins play an important role in the field of chromatography and show excellent separation performance. The design of simple and convenient methods for the efficient synthesis of novel chiral macrocycles for chromatographic separation is of great significance. In this work, a novel chiral polyimine macrocycle (PIMC) was designed and synthesized by the simply one-step reaction of 2,6-diformyl-4-tert-butylphenol with (S)-(-)-1,2-propanediamine. Then, it was bonded onto silica by the thiol-ene click reaction to construct a new chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). The chiral separation performance of the proposed CSP was examined by separating various racemates in the normal-phase (NP) and reversed-phase (RP) HPLC. In total, twelve and nine racemates, including ethers, esters, amines, alcohols, organic acids, ketones, and epoxides, were separated to varying degrees via NP-HPLC and RP-HPLC, respectively, Moreover, the CSP offered good chiral separation complementarity to Chiralcel OD-H and Chiralpak AD-H columns for resolution of these test racemates, and it can separate several racemic compounds that either cannot be separated or cannot be separated well be separated by the two commercially available columns. After the column was used for hundreds of injections, the relative standard deviations of the retention time and resolution were below 0.56 % and 0.45 %, respectively, showing the good reproducibility and stability of the CSP. This study provides a simple and convenient approach to synthesize a novel chiral macrocycle and CSP and also indicates the broad application prospects of such chiral PIMCs in HPLC chiral separation.

Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size.

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics.

Synthesis, Structure, Spectral, Redox, and Theoretical Studies of Sterically Crowded Decaaryl Triphyrin(2.1.1)s.

First examples of sterically crowded ß- and meso-arylated decaaryl triphyrin(2.1.1)s were synthesized by reacting ß-hexabromo meso-tetraaryl triphyrin(2.1.1) with five different aryl boronic acids in THF/toluene/H2O (1:1:1) in the presence of catalytic amount of Pd(PPh3)4/Na2CO3 at 80 °C for 12-24 h. The X-ray structure obtained for one of the decaaryl triphyrin(2.1.1)s revealed that the macrocycle exhibited saddle type of distortion due to steric crowding by bulky aryl substituents introduced at the six ß-carbons of meso-tetraaryl triphyrin(2.1.1) unlike almost planar structure observed for ß-unsubstituted meso-tetraaryl triphyrin(2.1.1). The absorption bands of decaaryl triphyrin(2.1.1)s were broadened and bathochromically shifted compared to meso-tetraaryl triphyrin(2.1.1) and the redox potentials were dependent on the kind of aryl substituents present at the ß-pyrrole carbons in decaaryl triphyrin(2.1.1)s. DFT and TD-DFT studies helped in understanding the alteration in the structure, spectral, and redox properties in decaaryl triphyrin(2.1.1)s compared to meso-tetraaryl triphyrin(2.1.1).

Isolation, Structure Elucidation, and Biological Activity of the Selective TACR2 Antagonist Tumonolide and its Aldehyde from a Marine Cyanobacterium.

The macrocyclic tumonolide (1) with enamide functionality and the linear tumonolide aldehyde (2) are new interconverting natural products from a marine cyanobacterium with a peptide-polyketide skeleton, representing a hybrid of apratoxins and palmyrolides or laingolides. The planar structures were established by NMR and mass spectrometry. The relative configuration of the stereogenically-rich apratoxin-like polyketide portion was determined using J-based configuration analysis. The absolute configuration of tumonolide (1) was determined by chiral analysis of the amino acid units and computational methods, followed by NMR chemical shift and ECD spectrum prediction, indicating all-R configuration for the polyketide portion, as in palmyrolide A and contrary to the all-S configuration in apratoxins. Functional screening against a panel of 168 GPCR targets revealed tumonolide (1) as a selective antagonist of TACR2 with an IC50 of 7.0 µM, closely correlating with binding affinity. Molecular docking studies established the binding mode and rationalized the selectivity for TACR2 over TACR1 and TACR3. RNA sequencing upon treatment of HCT116 colorectal cancer cells demonstrated activation of the pulmonary fibrosis idiopathic signaling pathway and the insulin secretion signaling pathway at 20 µM, indicating its potential to modulate these pathways.

Facile Synthesis and Global Aromaticity of Aza-Superbenzene and Aza-Supernaphthalene at Different Oxidation States.

All-benzenoid polycyclic aromatic hydrocarbons or macrocycles usually display localized aromaticity. On the other hand, incorporation of quinoidal units into the skeleton could lead to effective electron delocalization and global (anti)aromaticity. In this work, fully π-conjugated macrocycle 1 and bismacrocycle 2 containing both para-quinodimethane and triphenylamine units are efficiently synthesized mainly through intermolecular Friedel-Crafts alkylation reaction. They can be considered as a tetraazasuperbenzene and a hexaazasupernaphthalene, respectively, due to their similar geometry and electronic structures to the benzene and naphthalene. X-ray crystallographic analyses reveal a largely planar geometry for both 1 and 2 and variable-temperature NMR measurements disclose slow dynamic processes owing to restricted ring flipping of the phenyl rings. 1 and 2 can be easily oxidized into higher-oxidation-state species. NMR and theoretical calculations indicate that 12+ and 14+ show global anti-aromaticity and aromaticity, respectively, with a dominant 32π and 30π conjugation pathway, while for the bismacrocycle 2, its dication 22+, tetracation 24+ and hexacation 26+ exhibit global aromaticity, antiaromaticity, and aromaticity with a 54π, 52π and 50π conjugation pathway along the outermost backbone, respectively.

Designed Synthesis of an Aluminum Molecular Ring Based Rotaxane and Polyrotaxane.

Mechanically interlocked molecules, such as rotaxanes, have drawn significant attention within supramolecular chemistry. Although a variety of macrocycles have been thoroughly explored in rotaxane synthesis, metal-organic macrocycles remain relatively under-investigated. Aluminum molecular rings, with their inner cavities and numerous binding sites, present a promising option for constructing rotaxanes. Here, we introduce an innovative "ring-donor···axle-acceptor" motif utilizing Al8 molecular rings, enabling the stepwise assembly of molecules, complexes, and polymers through tailored coordination chemistry. This novel approach can not only be applied to macrocycle-based systems like catenanes but also enhance specific functionalities progressively.

Post-Synthetic Modification of Calix[4]arene Framework by Iridium-Mediated Alkyne Insertion into an Inert C-C Bond: A Novel Strategy for Unsymmetrical Macrocycles.

As a novel synthetic method for unsymmetrical macrocycles, we herein developed a post-synthetic modification of calix[4]arenes by insertion of a terminal alkyne into an inert C(methylene)-C(aryl) bond of the macrocyclic framework. In this transformation, C-iridated calix[4]arenes, readily synthesized through C-H bond activation of the parent calix[4]arene, undergoes C(methylene)-C(aryl) bond cleavage followed by insertion of an alkyne to provide a ring-expanded calix[4]arene complex. Removal of the iridium metal from the resulting complex was readily accomplished by a simple treatment with an acid. The developed sequential method affords novel unsymmetrical, monofunctionalized macrocyclic compounds via 3 steps from the parent calix[4]arene in good yield. The unique unsymmetrical structures of the alkyne-inserted macrocycles were evaluated by X-ray single crystal analyses. On the basis of theoretical calculations, we propose a reaction mechanism involving an uncommon C-C bond cleavage step through δ-carbon elimination for the ring enlargement process.

Fabrication of Azacrown Ether-Embedded Covalent Organic Frameworks for Enhanced Cathode Performance in Aqueous Ni-Zn Batteries.

Crown ethers (CEs), known for their exceptional host-guest complexation, offer potential as linkers in covalent organic frameworks (COFs) for enhanced performance in catalysis and host-guest binding. However, their highly flexible conformation and low symmetry limit the diversity of CE-derived COFs. Here, we introduce a novel C3-symmetrical azacrown ether (ACE) building block, tris(pyrido)[18]crown-6 (TPy18C6), for COF fabrication (ACE-COF-1 and ACE-COF-2) via reticular synthesis. This approach enables precise integration of CEs into COFs, enhancing Ni2+ ion immobilization while maintaining crystallinity. The resulting Ni2+-doped COFs (Ni@ACE-COF-1 and Ni@ACE-COF-2) exhibit high discharge capacity (up to 1.27 mAh ⋅ cm-2 at 8 mA ⋅ cm-2) and exceptional cycling stability (>1000 cycles) as cathode materials in aqueous alkaline nickel-zinc batteries. This study serves as an exemplar of the seamless integration of macrocyclic chemistry and reticular chemistry, laying the groundwork for extending the macrocyclic-synthon driven strategy to a diverse array of COF building blocks, ultimately yielding advanced materials tailored for specific applications.

Exploring the Spatial Arrangement of Simple 18-Membered Hexaazatetraamine Macrocyclic Ligands in Their Metal Complexes.

Hexaazamacrocyclic Schiff bases have been extensively combined with lanthanoid (Ln) ions to obtain complexes with a highly axial geometry. However, the use of flexible hexaazatetraamine macrocycles containing two pyridines and acyclic spacers is rather uncommon. Accordingly, we obtained [DyL(OAc)2]OAc·7H2O·EtOH and [DyLMe2(Cl)2]Cl·2H2O, where L and LMe2 are the 18-membered macrocycles 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane and 3,10-dimethyl-3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane, respectively, which contain ethylene and methylethylene spacers between their N3 moieties. [DyL(OAc)2]OAc·7H2O·EtOH represents the first crystallographically characterized lanthanoid complex of L, while [DyLMe2(Cl)2]Cl·2H2O contributes to increasing the scarce number of LnIII compounds containing LMe2. Furthermore, the crystal structure of L·12H2O was solved, and it was compared with those of other related macrocycles previously published. Likewise, the crystal structures of the DyIII complexes were compared with those of the lanthanoid and d-metal complexes of other 18-membered N6 donor macrocycles. This comparison showed some effect of the spacers employed, as well as the influence of the size of the ancillary ligands and the metal ion. Additionally, the distinct folding behaviors of these macrocycles influenced their coordination geometries. Moreover, the luminescent properties of [DyL(OAc)2]OAc·7H2O·EtOH and [DyLMe2(Cl)2]Cl·2H2O were also investigated, showing that both complexes are fluorescent, with the emission being sensitized by the ligands.

Identification of a macrocyclic compound targeting the lassa virus polymerase.

There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.

The coming of age of cyclic peptide drugs: an update on discovery technologies.

INTRODUCTION: Cyclic peptides are an established class of pharmaceuticals, with the ability to bind to a broader range of protein targets than traditional small molecules while also being capable of oral availability and cell penetration. Historically, cyclic peptide drugs have been discovered almost exclusively through natural product mining approaches; however, the last two decades have seen the development of display screening approaches capable of rapidly identifying de novo (i.e. not natural product derived) cyclic peptide ligands to targets of interest. AREAS COVERED: In this review, the authors describe the current clinical landscape for cyclic peptide pharmaceuticals. This article focuses on the discovery approaches that have led to the development of different classes of molecules and how the development of newer technologies, particularly phage and mRNA display, has broadened the clinical applicability of such molecules. EXPERT OPINION: The field of de novo cyclic peptide drug discovery is reaching maturity, with the first drugs identified through display screening approaches reaching the market in recent years. Many more are in clinical trials; however, significant technical challenges remain. Technological improvements will be required over the coming years to facilitate the identification of membrane permeable cyclic peptides capable of oral availability and targeting intracellular proteins.

Phenyl-Extended Resorcin[4]arenes: Synthesis and Highly Efficient Iodine Adsorption.

The continuous exploration of new analogs of calixarenes and pillararenes unlocks infinite opportunities in supramolecular chemistry and materials. In this work, we introduce a new class of macrocycle, phenyl-extended resorcin[4]arenes (ExR4), a unique and innovative design that incorporates unsubstituted phenylene moieties into the resorcin[4]arene scaffold. Single-crystal analysis reveals a chair-like conformation for per-methylated ExR4 (Me-ExR4) and a twisted "Figure-of-eight" shaped conformation for per-hydroxylated ExR4 (OH-ExR4). Notably, OH-ExR4 demonstrates exceptional adsorption capability toward I3 - ions in an aqueous solution, with a rapid kinetic rate of 1.18×10-2 g ⋅ mg-1 ⋅ min-1. Furthermore, OH-ExR4 shows excellent recyclability and potential as a stationary phase in column setups. The discovery of ExR4 opens up new avenues for constructing new macrocycles and inspires further research in functional adsorption materials for water pollutant removal.

Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.