Chiral Macrocycles for Enantioselective Recognition.

The efficient synthesis of chiral macrocycles with highly enantioselective recognition remains a challenge. We have addressed this issue by synthesizing a pair of chiral macrocycles, namely, R/S-BINOL[2], achieving total isolated yields of up to 62% through a two-step reaction sequence. These macrocycles are readily purified by column chromatography over silica gel without the need for chiral separation, thus streamlining the overall synthesis. R/S-BINOL[2] demonstrated enantioselective recognition toward chiral ammonium salts, with enantioselectivity (KS/KR) values reaching up to 13.2, although less favorable separations were seen for other substrates. R/S-BINOL[2] also displays blue circularly polarized luminescence with a |glum| value of up to 2.2 × 10-3. The R/S-BINOL[2] macrocycles of this study are attractive as chiral hosts in that they both display enantioselective guest recognition and benefit from a concise, high-yielding synthesis. As such, they may have a role to play in chiral separations.

Sequential Targeted Enzyme-Instructed Self-Assembly Supramolecular Nanofibers to Attenuate Intervertebral Disc Degeneration.

As an age-related disease, intervertebral disc degeneration is closely related to inflammation and aging. Inflammatory cytokines and cellular senescence collectively contribute to the degradation of intervertebral disc. Blocking this synergy reduces disc extracellular matrix damage caused by inflammation and aging. In this study, drug-loaded nanofibers with sequential targeting functions are constructed through intelligent response, hydrophilicity, and in situ self-assembly empowerment of flurbiprofen. The peptide precursor responds to the cleavage of overexpressed MMP-2 in the degenerative intervertebral disc microenvironment (intracellular and extracellular), resulting in the formation of self-assembled nanofibers that enable the on-demand release of flurbiprofen and COX-2 response. In vitro, Comp. 1 (Flurbiprofen-GFFYPLGLAGEEEERGD) reduces the expression of inflammation-related genes and proteins and the polarization of M1 macrophages by competitively inhibiting COX-2 and increases the expression of extracellular matrix proteins COL-2 and aggrecan. Additionally, it can reduce the expression of Senescence-Associated Secretory Phenotype and DNA damage in aged nucleus pulposus cells and promote the recovery of proliferation and cell cycle. In vivo, drug-loaded nanofibers delay intervertebral disc degeneration by inhibiting inflammation and preventing the accumulation of senescent cells. Therefore, the sequentially targeted self-assembled drug-loaded nanofibers can delay intervertebral disc degeneration by blocking the synergistic effect of inflammatory cytokines and cellular senescence.

General and Modular Synthesis of Covalent Organic Cages for Efficient Molecular Recognition.

Cage-type structures based on coordination and dynamic covalent chemistry have the characteristics of facile and efficient preparation but poor stability. Chemically stable organic cages, generally involving fragment coupling and multi-step reactions, are relatively difficult to synthesize. Herein, we offer a general and modular strategy to customize covalent organic cages with diverse skeletons and sizes. First, one skeleton (S) module with three extension (E) modules and three reaction (R) modules are connected by one- or two-step coupling to get the triangular monomer bearing three reaction sites. Then one-pot Friedel-Crafts condensation of the monomer and linking module of paraformaldehyde produces the designed organic cages. The cage forming could be regulated by the geometrical configuration of monomeric blocks. The S-E-R angles in the monomer is crucial; only 120o (2,4-dimethoxyphen as reaction module) or 60o (2,5-dimethoxyphen as reaction module) angle between S-E-R successfully affords the resulting cages. By the rational design of the three modules, a series of organic cages have been constructed. In addition, the host-guest properties show that the representative cages could strongly encapsulate neutral aromatic diimine guests driven by solvophobic interactions in polar solvents, giving the highest association constant of (2.58 ± 0.18) × 105 M-1.

Chemoselective Construction of Polycyclic Heterocycles Containing a [6-6-5] or [7-6-5] Tricyclic Core Skeleton from a 2-Isocyanophenyl Propargylic Ester.

Functionalized isocyanide chemistry represents an important research area in organic synthesis. A structurally unique 2-isocyanophenl propargylic ester has been designed to incorporate the reactivity of isocyanide and propargylic ester. Thus, the reaction of 2-isocyanophenyl propargylic ester and 2-aminoaromatic aldimine facilitates the synthesis of a wide range of polycyclic benzo[b]indolo[3,2-h][1,6]naphthyridine derivatives. Furthermore, reacting with 2-hydroxyaromatic aldimine enables the divergent synthesis of both the aforementioned scaffolds and another structurally distinctive diazabenzo[f]naphtho[2,3,4-ij]azulenes featuring a [7-6-5] core skeleton. Experimental results and DFT calculations suggest that these transformations likely proceed via the in situ generation of a strained cyclopropen-imine species followed by [3+2] cycloaddition. Next, switchable nucleophilic attack/ring-expansion/aromatization and nucleophilic addition/ring-expansion/elimination account for the observed selectivity.

Macrocyclic Neutralizer to Polybrene via Direct Host-Guest Complexation.

Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 107 M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.

Vapochromic separation of toluene and pyridine azeotropes using adaptive macrocycle co-crystals.

The separation of toluene (Tol) and pyridine (Py) azeotropes is significant in the chemical industry. Herein, we present a new method for the energy-efficient separation of Tol and Py using pillar[5]arene-based adaptive macrocycle co-crystals (MCCs) that can selectively separate Py from a Py/Tol equimolar mixture with 99.2% purity, accompanied by vapochromic behavior from white to yellow.

Structurally diverse macrocycle co-crystals for solid-state luminescence modulation.

Organic co-crystals offer an opportunity to fabricate organic functional materials. Traditional co-crystals are generally packed following the segregated or mixed stacking mode, leading to the lack of structural and functional diversity. Herein, we report three sets of macrocycle co-crystals with identical co-constitutions. The macrocycle co-crystals differ in the stoichiometric ratios (2:1, 1:1, and 2:3) of the constituents and molecular packing modes. The co-crystals are constructed using triangular pyrene-macrocycle and 1,2,4,5-tetracyanobenzene exploiting exo-wall charge-transfer interactions. Interestingly, the three co-crystals exhibit distinct, tunable emission properties. The corresponding emission peaks appear at 575, 602, and 635 nm, covering yellow via orange to red. The X-ray diffraction analyses and the density functional theory calculations reveal the superstructure-property relationships that is attributed to the formation of different ratios of charge-transfer transition states between the donor and acceptor motifs, resulting in red-shifted luminescence.

Bioactive peptide relieves glucocorticoid-induced osteoporosis by giant macrocyclic encapsulation.

Bioactive peptides play a crucial role in the field of regenerative medicine and tissue engineering. However, their application in vivo and clinic is hindered by their poor stability, short half-life, and low retention rate. Herein, we propose a novel strategy for encapsulating bioactive peptides using giant macrocycles. Platelet-derived growth factor (PDGF) bioactive mimicking peptide Nap-FFGVRKKP (P) was selected as the representative of a bioactive peptide. Quaterphen[4]arene (4) exhibited extensive host-guest complexation with P, and the binding constant was (1.16 ± 0.10) × 107 M-1. In vitro cell experiments confirmed that P + 4 could promote the proliferation of BMSCs by 2.27 times. Even with the addition of the inhibitor dexamethasone (Dex), P + 4 was still able to save 76.94% of the cells in the control group. Compared to the Dex group, the bone mass of the mice with osteoporosis in the P + 4 group was significantly increased. The mean trabecular thickness (Tb.Th) increased by 17.03%, and the trabecular bone volume fraction (BV/TV) values increased by 40.55%. This supramolecular bioactive peptide delivery strategy provides a general approach for delivering bioactive peptides and opens up new opportunities for the development of peptide-based drugs.

Cross-catenation between position-isomeric metallacages.

The study of cross-catenated metallacages, which are complex self-assembly systems arising from multiple supramolecular interactions and hierarchical assembly processes, is currently lacking but could provide facile insights into achieving more precise control over low-symmetry/high-complexity hierarchical assembly systems. Here, we report a cross-catenane formed between two position-isomeric Pt(II) metallacages in the solid state. These two metallacages formed [2]catenanes in solution, whereas a 1:1 mixture selectively formed a cross-catenane in crystals. Varied temperature nuclear magnetic resonance experiments and time-of-flight mass spectra are employed to characterize the cross-catenation in solutions, and the dynamic library of [2]catenanes are shown. Additionally, we searched for the global-minimum structures of three [2]catenanes and re-optimized the low-lying structures using density functional theory calculations. Our results suggest that the binding energy of cross-catenanes is significantly larger than that of self-catenanes within the dynamic library, and the selectivity in crystallization of cross-catenanes is thermodynamic. This study presents a cross-catenated assembly from different metallacages, which may provide a facile insight for the development of low-symmetry/high-complexity self-assemble systems.

Efficient macrocyclization facilitated by skeleton preorganization.

Reported here is the efficient macrocyclization facilitated by skeleton preorganization. A pyridylcarbazole macrocycle and a phenylpyridylcarbazole macrocycle was synthesized in yield up to 75%. Single-crystal structures and theoretic computation uncovered that the skeleton preorganization promoted the formation of cyclization-favorable conformation of noncyclic precursors via π⋯π interactions. This result provided a new approach for the efficient syntheses of macrocycles.

Modular Synthesis of Biphen[n]arenes Directed by Five-Membered Heterocycles.

Modular synthesis of novel biphen[n]arenes (n = 2-4) with customizable heterocycle blocks, functional skeletons, binding sites, and topological structures could be facilely achieved through the rational design and replacement of reaction modules (furan and thiophene), functional modules (substituted benzene, biphenyl, and naphthalene), and linking modules (methylene). These biphen[n]arenes were characterized by NMR, HRMS, and X-ray crystalline diffraction, complemented by DFT calculations. Their photophysical properties were thoroughly studied.

Phosphorescence enhancement of pyridinium macrocycles by poly(vinylalcohol).

A phosphorescence enhancement of pyridinium macrocycle/monomer phosphors is realized with up to 14.7-fold prolonging of the phosphorescence lifetimes and visible afterglow by doping into a poly(vinylalcohol) (PVA) matrix. The abundant hydrogen-bonding interactions and electrostatic interactions between the phosphors and the PVA suppressed the nonradiative decay processes, slowed down the radiative decay and nonradiative decay of triplet states, and therefore promoted the long-lived RTP.

Synthesis of a water-soluble naphthalene-based macrocycle and its host-guest properties.

Reported here is the synthesis of a naphthalene-based macrocycle bearing anionic carboxylato groups on the rims along with its complexation with cationic guests in aqueous media. The macrocycle could strongly bind guests in a molecular clip model with association constants of 106-107 M-1.

Separation of Cyclohexanone and Cyclohexanol by Adaptive Pillar[5]arene Cocrystals Accompanied by Vapochromic Behavior.

The separation of cyclohexanone (CHA-one) and cyclohexanol (CHA-ol) mixtures is of great importance in the chemical industry. Current technology exploits multiple steps of energy-intensive rectification due to their close boiling points. Herein, we report a new and energy-efficient adsorptive separation method employing binary adaptive macrocycle cocrystals (MCCs) built with π-electron-rich pillar[5]arene (P5) and an electron-deficient naphthalenediimide derivative (NDI) that can selectively separate CHA-one from an equimolar CHA-one/CHA-ol mixture with >99% purity. Intriguingly, this adsorptive separation process is accompanied by vapochromic behavior from pink to dark brown. Single-crystal and powder X-ray diffraction analyses reveal that the adsorptive selectivity and vapochromic property are derived from the CHA-one vapor inside the cocrystal lattice voids triggering solid-state structural transformations to yield charge-transfer (CT) cocrystals. Moreover, the reversible transformations make the cocrystalline materials highly recyclable.

Water-soluble terphen[3]arene macrocycle: a versatile reversal agent of neuromuscular blockers.

Herein we report the design and synthesis of a terphen[n]arene derivative functionalised with sulfate acid ester groups. This water-soluble terphen[3]arene host effectively encapsulates a multitude of neuromuscular blocking agents (NMBAs) with high affinity, showing great potential as a NMBAs reversal agent in pharmaceutical research.

Macrocycle with Equatorial Coordination Sites Provides New Opportunity for Structure-Diverse Metallacages.

Reported here is the synthesis of a macrocycle with equatorial coordination sites for the construction of self-assembled metallacages. The macrocycle is prepared via a post-modification on the equator of biphen[n]arene. Utilizing this macrocycle as a ligand, three prismatic cages and one octahedral cage were synthesized by regulating the geometric structures and coordination number of metal acceptors. The multi-cavity configuration of prismatic cage was revealed by single-crystal structure. We prove that a macrocycle with equatorial coordination sites can be an excellent building block for synthesizing structure-diverse metallacages. Our results provide a typical example and a general method for the design and synthesis of metallacages.

Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors.

Since bacteria in biofilms are inherently resistant to antibiotics and biofilm-associated infections pose a serious threat to global public health, new therapeutic agents and schemes are urgently needed to meet clinical requirements. Here two quaternary ammonium-functionalized biphen[n]arenes (WBPn, n=4, 5) were designed and synthesized with excellent anti-biofilm potency. Not only could they inhibit the assembly of biofilms, but also eradicate intractable mature biofilms formed by Gram-positive S. aureus and Gram-negative E. coli bacterial strains. Moreover, they could strongly complex a conventional antibiotic, cefazolin sodium (CFZ) with complex stability constants of (7.41±0.29)×104  M-1 for CFZ/WBP4 and (4.98±0.49)×103  M-1 for CFZ/WBP5. Combination of CFZ by WBP4 and WBP5 synergistically enhanced biofilm eradication performance in vitro and statistically improved healing efficacy on E. coli-infected mice models, providing a novel supramolecular strategy for combating biofilm-associated infections.

Host-guest complexation of cyclophosphamide by carboxylatopillar[6]arene for increasing stability and enhancing its curative effect on breast carcinoma.

Advanced chemotherapy strategies are in urgent demand for improving antitumor efficacy on breast carcinoma. Herein, a drug delivery system comprised of host-guest complex between carboxylated pillar[6]arene (CP6A) and cyclophosphamide (CTX) has been designed with view to overcoming several drawbacks associated with this antitumor agent. NMR and fluorescence titration served to confirm the complexation of CTX/CP6A. Baring CP6A did not affect cell viability as inferred from comparison studies carried out in human normal mammary epithelial cells and breast adenocarcinoma cells. Stability experiment proved that complexation of CTX by CP6A could increase the inherent stability of CTX in phosphate buffer (pH = 7.4) at 37 °C in a statistically significant way. In vivo research confirmed that CTX/CP6A was not only able to promote antitumor efficacy but also reduce CTX-related systemic toxicity on breast adenocarcinoma cells derived subcutaneous tumor xenograft mouse models. This drug delivery system could also be extended to other clinical chemotherapeutic agents and it was expected to provide salutary profits for more patients.

Facile synthesis of heterogeneous macrocycles for intramolecular energy transfer.

Heterogeneous macrocycles with fluorenone and fluorenol functional groups are synthesized by two facile methods involving post-modification on the macrocycles and one-pot co-cyclization from different monomers. Significantly, benefitting from the well-matched absorption/emission spectra and close distance of fluorenone/fluorenol moieties, the obtained heterogeneous macrocycles exhibit intriguing intramolecular energy transfer (ET) and fluorescence enhancement.

Cascade reaction of o-enoyl arylisocyanide and o-hydroxy aromatic aldimine: diastereoselective access to a polycyclic spirobenzoxazine chromeno[4,3-b]pyrrole derivative.

A series of structurally unusual spirobenzoxazine chromeno[4,3-b]pyrrole derivatives have been efficiently constructed in a single operation from readily available starting materials. This domino transformation forms successively three new rings and provides a fast and economic strategy with excellent diastereoselectivity.