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A tetracationic macrocycle can include clinically used photodynamic agents, alleviating their posttreatment phototoxicity and maintaining their photodynamic efficacy.

ConspectusIn past decades, regular porous architectures have received a great amount of attention because of their versatile functions and applications derived from their efficient adsorption of various guests. However, most reported porous architectures exist only in the solid state. Therefore, their applications as biomaterials may face several challenges, such as phase separation, slow degradation, and long-term accumulation in the body. This Account summarizes our efforts with respect to the development and biomedical applications of water-soluble 3D diamondoid supramolecular organic frameworks (

Heparins are natural and partially degraded polyelectrolytes that consist of sulfated polysaccharide backbones. However, as clinically used anticoagulants, heparins are associated with clinical bleeding risks and thus require rapid neutralization. Protamine sulfate is the only clinically approved antidote for unfractionated heparin (UFH), which not only may cause severe adverse reactions in patients, but also is only partially effective against low molecular weight heparins (LMWHs). We here present the facile synthesis of four porous multicationic dynamic covalent polymers (DCPs) from the condensation of tritopic aldehyde and acylhydrazine precursors. We show that, as new water-soluble polymeric antidotes, the new DCPs can effectively include both UFH and LMWHs and thus reverse their anticoagulating activity, which is confirmed by the activated partial thromboplastin time and thromboelastographic assays as well as mouse tail transection assay (bleeding model). The neutralization activities of two of the DCPs were found to be overall superior to that of protamine and have wider concentration windows and good biocompatibility. This pore-inclusion neutralization strategy paves the way for the development of water-soluble polymers as universal heparin binding agents.

A symmetric organic dye can form a highly stable homotrimer in the cavity of CB[10], which exhibits unique multicolour fluorescence different from that of the single molecule or its dimer.

Phase I-III clinical studies show that aldoxorubicin (AlDox), a prodrug of doxorubicin (Dox), displays reduced cardiotoxicity compared to Dox, but does not demonstrate an overall survival benefit in patients. Here we report that three-dimensional supramolecular organic frameworks (SOFs) can conjugate AlDox through quantitative thiol-maleimide addition to afford two polymeric prodrugs of Dox. The previously established ability of SOFs in overcoming the multidrug resistance of tumor cells is utilized to achieve efficient intracellular delivery of the conjugated AlDox, which releases Dox as an active agent through acid-responsive hydrolysis of the hydrazone bond of AlDox within tumor cells.

Broad-spectrum agents for the reversal of residual curarization induced by neuromuscular blocking agents are of great significance. Here, we report a highly water-soluble cucurbit[8]uril (CB[8]) derivative as a broad-spectrum neuromuscular block reversal agent induced by both benzylisquinolinium and aminosteroid neuromuscular block agents by the supramolecular sequestration strategy. The UV/Vis competition titration assays suggest the high binding affinity of the CB[8] derivative toward both benzylisquinolinium-type cisatracurium besylate and aminosteroid-type rocuronium, vecuronium, and pancuronium, at the level of 10

Accurate control of the layer number of orderly stacked 2D polymers has been an unsettled challenge in self-assembly. Herein we describe the fabrication of a bilayer 2D supramolecular organic framework from a monolayer 2D supramolecular organic framework in water by utilizing the cooperative coordination of a rod-like bipyridine ligands to zinc porphyrin subunits of the monolayer network. The monolayer supramolecular framework is prepared from the co-assembly of an octacationic zinc porphyrin monomer and cucurbit[8]uril (CB[8]) in water through CB[8]-encapsulation-promoted dimerization of 4-phenylpyridiunium subunits that the zinc porphyrin monomer bear. The bilayer 2D supramolecular organic framework exhibits structural regularity in both solution and the solid state, which is characterized by synchrotron small-angle X-ray scattering and high-resolution transmission electron microscopic techniques. Atomic force microscopic imaging confirms that the bilayer character of the 2D supramolecular organic framework can be realized selectively on the micrometer scale.

A porous supramolecular framework has been for the first time revealed to undergo interpenetration in crystal and non-interpenetration in solution. A new supramolecular organic framework Bu-SOF has been constructed from the co-assembly of a tetracationic tetrahedral monomer and cucurbit[8]uril (CB[8]) in water through the encapsulation of two anti-parallel n-butyl chains by CB[8]. X-ray diffraction analysis reveals that Bu-SOF forms 3-fold interpenetrated networks in crystals grown by evaporation of its solution in water. 1H NMR, dynamic light scattering and isothermal titration calorimetric experiments confirm that Bu-SOF is also formed in water. Solid samples, prepared by lyophilizing the aqueous solution of Bu-SOF, can adsorb nanoscaled organic dyes, supporting the porosity of the framework and thus non-interpenetration in solution. The avoidance of interpenetration of Bu-SOF in solution has been attributed to the filling of water inside the porous framework as well as the electrostatic repulsion of the appended bipyridinium units of the tetrahedral building block.

Selective preparation of two-dimensional polymers (2DPs) and supramolecular polymers (2DSPs) with defined thickness is crucially important for controlling and maximizing their functions, yet it has remained as a synthetic challenge. In the past decade, several approaches have been developed to allow selective preparation of discrete monolayer 2DPs and 2DSPs. Recently, crystal exfoliation and self-assembly strategies have been employed to successfully prepare bilayer 2DP and 2DSP, which represent the first step towards the controlled "growth" of 2D polymers from the thinnest monolayers to thicker few-layers along the third dimension. This Concept review discusses the concept of accurate synthesis of 2D polymers with defined layers. Advances in this research area will pave the way to rational synthetic strategies for 2D polymers with controlled thickness.

Supramolecular sequestration and reversal of neuromuscular block (NMB) have great clinical applications. Water-soluble flexible organic frameworks (FOFs) cross-linked by disulfide bonds are designed and prepared. Different linker lengths are introduced to FOFs to give them varied pore sizes. FOFs are anionic nanoscale polymers and capable of encapsulating cationic neuromuscular blocking agents (NMBAs), including rocuronium (Roc), vecuronium (Vec), pancuronium (Panc) and cisatracurium (Cis). A host-guest study confirms that FOFs bind NMBAs in water. The multivalency interaction between FOFs and NMBAs is able to sequester NMBAs, and prevent them from escaping. These FOFs are non-toxic and biocompatible. Animal studies show that FOFs are effective for the reversal of NMB induced by Roc, Vec and Cis, which shorten the time to a train-of-four ratio of 0.9 by 2.6, 3.8 and 5.7-fold compared to a placebo, respectively.

Porous organic polymers (POPs) have attracted increasing attention and emerged as a new research area in polymer chemistry. During the past decade, the intense desirability for application in aqueous scenarios has spawned the development of a specific class of POPs

Heparins are widely used anticoagulants for surgical procedures and extracorporeal therapies. However, all of them have bleeding risks. Protamine sulfate, the only clinically approved antidote for unfractionated heparin (UFH), has adverse effects. Moreover, protamine can only partially neutralize low-molecular-weight heparins (LMWHs) and is not effective for fondaparinux. Here, an inclusion-sequestration strategy for efficient neutralization of heparin anticoagulants by cationic porous supramolecular organic frameworks (SOFs) and porous organic polymers (POPs) is reported. Isothermal titration calorimetric and fluorescence experiments show strong binding affinities of these porous polymers toward heparins, whereas dynamic light scattering and zeta potential analysis confirm that the heparin sequences are adsorbed into the interior of the porous hosts. Activated partial thromboplastin time, anti-FXa, and thromboelastography assays indicate that their neutralization efficacies are higher than or as high as that of protamine for UFH and generally superior to protamine for LMWHs and fondaparinux, which is further confirmed by tail-transection model in mice and ex vivo aPTT or anti-FXa analysis in rats. Acute toxicity evaluations reveal that one of the SOFs displays outstanding biocompatibility. This work suggests that porous polymers can supply safe and rapid reversal of clinically used heparins, as protamine surrogates, providing an improved approach for their neutralization.

Three electron-rich donor molecules D1–D3, which consist of one, two or four 1,4-bis(carboxylatomethoxy)benzene units, respectively, have been prepared. Donor–acceptor interactions between the di-, tetra- and octaanionic donors and electron-deficient bipyridinium derivatives A1–A3, which bear two methyl, benzyl, or 4-formylphenyl subunits, respectively, have been investigated using X-ray diffraction analysis (for the complex of D2 and A1) and 1H NMR and absorption experiments. It was revealed that D1 and D2 formed 1 : 1 donor–acceptor complexes with the three acceptors, while D3 formed 1 : 2 complexes with them. All the complexes exhibited high water-solubility. The crystal structure of complex D1·A1 showed that the biphenyl unit of D1 and the bipyridinium unit of A1 stacked alternately in the new perfect face-to-face pattern. By using isothermal titration calorimetric titration experiments, association constants for the 1 : 1 and 1 : 2 complexes in water were determined to be as high as 1.3 × 104 M−1 and 2.6 × 1011 M−2, respectively. The results supported that the intermolecular ion-pair electrostatic attraction between the carboxylate anions and the bipyridinium dication remarkably enhanced the intermolecular donor–acceptor interaction in water.

A new acylhydrazone fluorescence probe, SPBH, was synthesized from salicylaldehyde and 4-(pyridin-4-yl)benzohydrazide (PBH). SPBH exhibited high selectivity and a sensitive fluorescence response towards Al3+, even in the presence of other competing metal ions in DMF/H2O (1 : 1, v/v) medium. And, the chemosensor can even detect Al3+ in the intracellular region of human non-small cell lung cancer H460 cells. The binding phenomenon of SPBH was investigated by 1H NMR spectroscopy and HR-MS. Mass spectrometry analysis showed a 1 : 1 complex formation of SPBH with Al3+. The Job plot also confirmed its 1 : 1 interaction. This SPBH/Al3+ complex exhibited excellent fluorescence “turn-off” properties towards the F− anion. Thus, SPBH acts as a sequential fluorescence “Off–On–Off” probe. The limits of detection for Al3+ and F− were calculated from the titration curve and found to be 1.1 × 10−7 M and 1.47 × 10−6 M, respectively.

Morpholine and methylpiperazine are among the most important structural parts of different drugs including organic chemotherapeutic agents. In the current study we incorporated these entities as co-ligand and a series of structurally related mono- and di-metallic square planner Pt(II) complexes (Pt(II)(salicylaldimine)(morpholine)Cl C1a–C3a, Pt(II)(salicylaldimine) (methylpiperazine)Cl C1b–C3b, di-metallic Pt(II)2(bis-salicylaldimine)(morpholine)2Cl2 C4a and Pt(II)2(bis-salicylaldimine)(methylpiperazine)2Cl2 C4b were prepared. These complexes were characterized by 1H, 13C, 19F, 2D NOESY NMR, HR ESI-MS and elemental analyses, while structures of C2a, C3a and C4b were determined by single crystal X-ray analysis. All these complexes were studied for their in vitro cytotoxic effect on breast (MCF-7), liver (HepG2) and lung (A549) cancer cell lines. All these complexes showed considerable cytotoxic effect on these tested cancer cell lines comparable to cisplatin. Moreover three complexes C1a, C4a and C1b were studied in details. Time- and dose-dependent study was performed for C1a, C4a and C1b. These complexes induced the expression of p53 that suppresses cancer cell growth. Induction of PUMA gene and repression of MYC oncogene suggested that these complexes targeted different genes to suppress cancer progression. TUNEL assay showed induction of apoptosis and invasion analysis showed reduction in invasion ability of breast cancer cells treated with C1a, C4a or C1b. Importantly, these novel complexes suppressed the expression of EMT and metastasis promoter genes. Similarly these complexes induced autophagy by enhancing the expression of autophagy related genes such as beclin, atg-5 and atg-7. The E. coli growth retardation study showed stronger growth inhibitory effects and subsequently resulted in filamentous morphology of bacterial cells. Gel electrophoresis study proved the interaction of these complexes with DNA. All these analysis revealed anticancer potencies of this class of complexes.

A polycationic two-dimensional (2D) covalent organic framework (PC-COF) has been prepared via the formation of imine bonds from the condensation of a rigid triangular triamine and a 4,4′-bipyridinium (BIPY)-derived dialdehyde. The new polycationic COF has a honeycomb structure with a pore diameter of about 5.8 nm. Powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) experiments supported that the 2D layer structures stack into 3D porous frameworks and the adjacent BIPY dications stack in an eclipsed pattern, with chloride counterions being sandwiched in between the layers. PC-COF is highly stable in water, and functions as a robust adsorbent, as demonstrated by its high uptake capacity (>97%) towards a range of anionic organic dye pollutants from water even at a low concentration (3.2 × 10−5 M). Moreover, the adsorbed guests could be released at high recovery rate, such as in the case of methyl orange.

Cubic metal-covalent-supramolecular organic framework (MCSOF-1) hybrid has been created from the reaction of two molecular components and subsequent co-assembly with cucurbit[8]uril (CB[8]) in water. In the presence of CB[8], [Ru(bpy)3]2+ -based acylhydrazine 1·2Cl reacted with aldehyde 2·Cl to quantitatively yield six-armed precursor 3·8Cl through the generation of MCSOF-1. MCSOF-1 combines the structural features of metal-, covalent- and supramolecular organic frameworks. Its periodicity in water and in the solid state was confirmed by synchrotron X-ray scattering and diffraction experiments. MCSOF-1 could enrich discrete anionic polyoxometalates (POMs), maintain periodicity in acidic medium, and remarkably facilitate visible light-induced electron transfer from its [Ru(bpy)3]2+ units to enriched POMs, leading to enhanced catalysis of the POMs for the reduction of proton to H2 in both aqueous (homogeneous) and organic (heterogeneous) media.

Enrichment of molecular photosensitizers and catalysts in a confined nanospace is conducive for photocatalytic reactions due to improved photoexcited electron transfer from photosensitizers to catalysts. Herein, the self-assembly of a highly stable 3D supramolecular organic framework from a rigid bipyridine-derived tetrahedral monomer and cucurbit[8]uril in water, and its efficient and simultaneous intake of both [Ru(bpy)3 ]2+ -based photosensitizers and various polyoxometalates, that can take place at very low loading, are reported. The enrichment substantially increases the apparent concentration of both photosensitizer and catalyst in the interior of the framework, which leads to a recyclable, homogeneous, visible light-driven photocatalytic system with 110-fold increase of the turnover number for the hydrogen evolution reaction.

Rigid linear compounds G1 and G2, which contained two 4-phenylpyridinium (PhPy+ ) units, have been prepared to investigate their binding with cucurbit[8]uril (CB[8]). X-ray crystallographic structures revealed that in the solid state both compounds were included by CB[8], through antiparallel stacking, to form 2:2 quaternary complexes (G1)2 @(CB[8])2 and (G2)2 @(CB[8])2 . For the former complex, CB[8] entrapped G1 by holding two heterodimers of its Py+ and benzyl units, which were at opposite ends of the backbone. In contrast, for the first time, the second complex disclosed parallel stacking of two cationic Py+ units of G2 in the cavity of CB[8] in the solid state, despite the generation of important electrostatic repulsion. Isothermal titrations in water afforded high apparent association constants of 4.36×106 and 6.43×106 m-1 for 1:1 complexes G1@CB[8] and G2@CB[8], respectively, and 1 H NMR spectroscopy experiments in D2 O confirmed a similar stacking pattern to that observed in the solid state. A previous study and crystal structures of the 2:1 complexes formed between three new controls, G3-5, and CB[8] did not display such unusual stacking of the cationic Py+ unit; this may be attributed to the multivalency of the two CB[8] encapsulation interactions.

© 2017 The Royal Society of Chemistry. We present the postmodification of a diamondoid 3D supramolecular organic framework (SOF) to append [Ru(BPY)3]2+ groups through the formation of a hydrazone bond. The resulting SOF works as an efficient recyclable heterogeneous catalyst for visible-light-induced reduction of aromatic azides to amines.

An efficient procedure has been developed for the preparation of tetrasubstituted unsymmetrical 1,4-enediones via copper-promoted autotandem catalysis and air as the oxidant. Various N-nucleophiles are compatible with this reaction, such as morpholine, piperidine, pyrrolidine, arylamines, pyrazole, imidazole, benzimidazole, and benzotriazole. This reaction also has significant advantages in easily available substrates, atom economy, bond-forming efficiency, and environmental benignity.

Twelve new ent-abietane diterpenoids, chlorabietins A–L (1–12), were isolated from the roots of Chloranthus oldhamii. Their structures and absolute configurations were determined by extensive spectroscopic analyses, X-ray diffraction, and experimental/calculated electronic circular dichroism (ECD) spectroscopy. Among the new isolates, chlorabietins D (4) and E (5) are the first two naturally occurring 8-spiro-fused 9,10-seco-ent-abietanes containing an unexpected cis-fused A/B ring system. Chlorabietin F (6) is a rare chinane-type diterpenoid featuring a hitherto unknown C-ring cleavage between C-13 and C-14, which might be derived from a common precursor of the above spiro-diterpenoid epimers 4 and 5, and their biosynthetic relationships are briefly discussed. Meanwhile, chlorabietin I (9) is the first representative of the abietane-type diterpenoids possessing a tetrahydrofurano function bridging C-6 and C-19. Chlorabietins B (2), C (3), F (6), and G (7) showed anti-neuroinflammatory effects by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine BV-2 microglial cells, with IC50 values ranging from 16.4 to 33.8 μM.

Twelve new ent-abietane diterpenoids, chlorabietins A–L (1–12), were isolated from the roots of Chloranthus oldhamii. Their structures and absolute configurations were determined by extensive spectroscopic analyses, X-ray diffraction, and experimental/calculated electronic circular dichroism (ECD) spectroscopy. Among the new isolates, chlorabietins D (4) and E (5) are the first two naturally occurring 8-spiro-fused 9,10-seco-ent-abietanes containing an unexpected cis-fused A/B ring system. Chlorabietin F (6) is a rare chinane-type diterpenoid featuring a hitherto unknown C-ring cleavage between C-13 and C-14, which might be derived from a common precursor of the above spiro-diterpenoid epimers 4 and 5, and their biosynthetic relationships are briefly discussed. Meanwhile, chlorabietin I (9) is the first representative of the abietane-type diterpenoids possessing a tetrahydrofurano function bridging C-6 and C-19. Chlorabietins B (2), C (3), F (6), and G (7) showed anti-neuroinflammatory effects by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine BV-2 microglial cells, with IC50 values ranging from 16.4 to 33.8 μM.

Carbon dots (CDs) with tunable photoluminescence (PL) and a quantum yield of up to 35% in water were hydrothermally synthesized in one pot and separated via silica column chromatography. These separated CDs emitted bright and stable luminescence in gradient colors from blue to red under a single-wavelength UV light. They exhibited high optical uniformity; that is, every sample showed only one peak in the PL excitation spectrum, only one peak in the excitation-independent PL emission spectrum, and similar monoexponential fluorescence lifetimes. Although these samples had similar distributions of particle size and graphite structure in their carbon cores, the surface state gradually varied among the samples, especially the degree of oxidation. Therefore, the observed red shift in their emission peaks from 440 to 625 nm was ascribed to a gradual reduction in their band gaps with the increasing incorporation of oxygen species into their surface structures. These energy bands were found to depend on the surface groups and structures but not on the particle size, not as in traditional semiconductor quantum dots. In addition, because of their excellent PL properties and low cytotoxicity, these CDs could be used to image cells in different colors under a single-wavelength light source, and the red-emitting CDs could be used to image live mice because of the strong penetration capability of their fluorescence.

The mechanism of the samarium-catalyzed 1,5-regioselective azide-alkyne [3 + 2]-cycloaddition (SmAAC) reaction has been examined with quantum mechanical calculations at the B3LYP/6-31+G(d,p) level of theory with ECP51MWB on Sm. Four stepwise pathways were located, with two leading to the 5-endocyclic 1,5-disubstituted 1,2,3-triazole product PSmL2 (paths 1 and 2) and the other two to the exocyclic product ExoPSmCl2 (path 3) as well as 1,4-disubstituted 1,2,3-triazole RegPSmL2 (path 4), respectively. Among them, path 2 (R-COM1-TS12-COM2-TS23-COM3-TS3P-PSmL2) is the most favored one both in the gas phase and in toluene solution, which is in good agreement with the experimental data. Moreover, 1,1-insertion forming COM2 in path 2 is the rate-determining step. The computational results also infer that the participation of samarium catalyst changes the distribution of the electrostatic potential on the reactants' surface, which determines the polarization direction of the reactants and formation of different intermediates (COM1 and RegCOM1), and finally affects the regioselectivity. When solvent corrections for toluene are considered, the 1,1-insertion process is discouraged, while the intramolecular [1,3]-shift reaction is facilitated.

An efficient procedure has been developed for the preparation of tetrasubstituted unsymmetrical 1,4-enediones via copper-promoted autotandem catalysis and air as the oxidant. Various N-nucleophiles are compatible with this reaction, such as morpholine, piperidine, pyrrolidine, arylamines, pyrazole, imidazole, benzimidazole, and benzotriazole. This reaction also has significant advantages in easily available substrates, atom economy, bond-forming efficiency, and environmental benignity.

A novel copper-catalyzed synthesis of pyridopyrimidinones from 1,4-enediones and 2-amino-heterocycles is developed.

A copper-catalyzed domino synthesis of 4H-pyrido[1,2-a]pyrimidin-4-ones has been developed from 1,4-enediones and 2-aminoheterocycles with air as the oxidant.