Porous Organic Cage as an Efficient Platform for Industrial Radioactive Iodine Capture.

Herein, we firstly develop porous organic cage (POC) as an efficient platform for highly effective radioactive iodine capture under industrial operating conditions (typically ≥150 °C), ≤150 ppmv of I2). Due to the highly dispersed and readily accessible binding sites as well as sufficient accommodating space, the constructed NKPOC-DT-(I-) (NKPOC=Nankai porous organic cage) demonstrates a record-high I2 uptake capacity of 48.35 wt % and extraordinary adsorption capacity of unit ionic site (~1.62) at 150 °C and 150 ppmv of I2. The I2 capacity is 3.5, 1.6, and 1.3 times higher than industrial silver-based adsorbents Ag@MOR and benchmark materials of TGDM and 4F-iCOF-TpBpy-I- under the same conditions. Furthermore, NKPOC-DT-(I-)Me exhibits remarkable adsorption kinetics (k1=0.013 min-1), which is 1.2 and 1.6 times higher than TGDM and 4F-iCOF-TpBpy-I- under the identical conditions. NKPOC-DT-(I-)Me thus sets a new benchmark for industrial radioactive I2 adsorbents. This work not only provides a new insight for effectively enhancing the adsorption capacity of unit functional sites, but also advances POC as an efficient platform for radioiodine capture in industry.

Pasteurella multocida activates Rassf1-Hippo-Yap pathway to induce pulmonary epithelial apoptosis.

Pasteurella multocida is an opportunistic zoonotic pathogen that primarily causes fatal respiratory diseases, such as pneumonia and respiratory syndromes. However, the precise mechanistic understanding of how P. multocida disrupts the epithelial barrier in mammalian lung remains largely unknown. In this study, using unbiased RNA-seq analysis, we found that the evolutionarily conserved Hippo-Yap pathway was dysregulated after P. multocida infection. Given the complexity of P. multocida infection associated with lung injury and systemic inflammatory processes, we employed a combination of cell culture models, mouse models, and rabbit models to investigate the dynamics of the Hippo-Yap pathway during P. multocida infection. Our findings reveal that P. multocida infection activates the Hippo-Yap pathway both in vitro and in vivo, by upregulating the upstream factors p-Mst1/2, p-Lats1, and p-Yap, and downregulating the downstream effectors Birc5, Cyr61, and Slug. Conversely, pharmacological inhibition of the Hippo pathway by XMU-MP-1 significantly rescued pulmonary epithelial cell apoptosis in vitro and reduced lung injury, systemic inflammation, and mouse mortality in vivo. Mechanistic studies revealed that P. multocida induced up-regulation of Rassf1 expression, and Rassf1 enhanced Hippo-Yap pathway through phosphorylation. Accordingly, in vitro knockdown of Rassf1 significantly enhanced Yap activity and expression of Yap downstream factors and reduced apoptosis during P. multocida infection. P. multocida-infected rabbit samples also showed overexpression of Rassf1, p-Lats1, and p-Yap, suggesting that P. multocida activates the Rassf1-Hippo-Yap pathway. These results elucidate the pathogenic role of the Rassf1-Hippo-Yap pathway in P. multocida infection and suggest that this pathway has the potential to be a drug target for the treatment of pasteurellosis.

Asymmetric Synthesis of Tertiary α-Hydroxylation-Cyclopentanones via Synergetic Catalysis of Chiral-at-Metal Rhodium(III) Complexes/Pyrrolidine.

Catalytic and asymmetric domino Michael/aldol reaction of 1,2-dicarbonyl compounds with α,ß-unsaturated ketones under the synergetic catalysis of chiral-at-metal rhodium complexes and pyrrolidine to deliver tertiary α-hydroxylation-cyclopentanones (45-89% yields with 81-99% ee and up to >20:1 dr) bearing three contiguous stereogenic centers had been established. Moreover, the scalability and practical utility of this protocol were well demonstrated by employing a gram-scale reaction and some representative transformations.

A general large-scale synthesis approach for crystalline porous materials.

Crystalline porous materials such as covalent organic frameworks (COFs), metal-organic frameworks (MOFs) and porous organic cages (POCs) have been widely applied in various fields with outstanding performances. However, the lack of general and effective methodology for large-scale production limits their further industrial applications. In this work, we developed a general approach comprising high pressure homogenization (HPH), which can realize large-scale synthesis of crystalline porous materials including COFs, MOFs, and POCs under benign conditions. This universal strategy, as illustrated in the proof of principle studies, has prepared 4 COFs, 4 MOFs, and 2 POCs. It can circumvent some drawbacks of existing approaches including low yield, high energy consumption, low efficiency, weak mass/thermal transfer, tedious procedures, poor reproducibility, and high cost. On the basis of this approach, an industrial homogenizer can produce 0.96 ~ 580.48 ton of high-performance COFs, MOFs, and POCs per day, which is unachievable via other methods.

Thiazole functionalized covalent triazine frameworks for C2H6/C2H4 separation with remarkable ethane uptake.

A highly stable thiazole functionalized covalent triazine framework, namely CTF-BT-500, was developed for C2H6/C2H4 separation, which exhibits a record-high ethane uptake (99.7 cm3 g-1) among all reported COFs at 298 K and 1 bar. This work not only presents an excellent C2H6-selective adsorbent, but also provides guidance for the construction of robust adsorbents for value-added gas purification.

Fischer's base-triggered formal (3+2) cycloadditions with 3-isothiocyanato oxindoles as acceptor-donor synthons.

Herein, previously unreported Fischer's base reactants serving as useful 2C building blocks in (3+2) cycloaddition reactions to build a library of bispiro[Fischer's base-oxindole] hybrids are described. These structurally intriguing products containing three adjacent quaternary stereocentres were smoothly afforded in up to 82% yield and >20 : 1 dr under catalyst-free conditions. Notably, the present protocol firstly employs 3-isothiocyanato oxindole serving as an acceptor and then as a donor in the formal (3+2) cycloadditions, allowing practical, straightforward access to structurally diverse cycloadducts. This work expands the applicability scope of 3-isothiocyanato oxindoles, which have been limited to behaving as donor/acceptor-based synthons in cycloadditions in previous work.

Organophosphine as an Alkyl Transfer Shuttle for the Direct ß-Alkylation of Chalcones Using Alkyl Halides.

We report an efficient alkyl transfer strategy for the direct ß-alkylation of chalcones using commercially available alkyl bromides as alkyl reagents. In this transformation, the ortho-phosphanyl substituent in the chalcones is crucial for controlling their reactivity and selectivity. It also serves as a reliable alkyl transfer shuttle to transform electrophilic alkyl bromides into nucleophilic alkyl species in the form of quaternary phosphonium salts and transfer the alkyl group effectively to the ß-position of the chalcones. This alkyl transfer strategy can be further extended to the alkenylation of ortho-phosphanyl benzaldehydes to assemble functionalized polyenes.

Asymmetric Formal (3 + 2) Cyclocondensation of Coumarin-3-Formylpyrazoles as 3-Carbon Partners with 3-Hydroxyoxindoles via Esterification/Michael Addition Sequence.

The first enantioselective formal (3 + 2) cyclocondensation involving α,ß-unsaturated pyrazoleamides as 3-carbon partners was accomplished in a stepwise fashion. The stepwise esterification/Michael addition sequence is promoted by Zn(OTf)2 and quinine-squaramide derivative, respectively. The protocol enables access to spiro-fused pentacyclic spirooxindoles from coumarin-3-formylpyrazoles and 3-hydroxyoxindoles in good to satisfactory overall yields (up to 91%) with excellent dr (all cases >20:1 dr) and high ee values (up to 99%). Mechanistic investigations contributed to shedding light on the enantioselective event of the process.

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons.

Here, we demonstrate the first example of 3-isothiocyanato thiobutyrolactone serving as a useful building block in the Michael/cyclization reaction with alkylidene pyrazolones for the enantioselective construction of optically active structural bispiro[pyrazolone-thiobutyrolactone] skeletons containing three contiguous stereocenters with two spiroquaternary stereocenters. These products were smoothly afforded in up to 90% yield, >20 : 1 dr and >99% ee with chiral squaramide as the catalyst under mild conditions. Notably, this is also the first example of the merger of a spirocyclic pyrazolone scaffold with a spirocyclic thiobutyrolactone scaffold, potentially useful in medicinal chemistry.

Advances in chromone-based reactants in the ring opening and skeletal reconstruction reaction: access to skeletally diverse salicyloylbenzene/heterocycle derivatives.

Salicyloylbenzene/heterocycles are privileged scaffolds found in many natural products and bioactive molecules. Numerous useful approaches for the preparation of these privileged scaffolds have been developed in recent years. Among these approaches, chromone-based reactants have demonstrated their importance in the synthesis of these salicyloylbenzene/heterocycle scaffolds with structural complexity and potential biological appeal. In this review, the recent advances in the synthesis of salicyloylbenzene/heterocycles are summarized and discussed according to the chromone-based reactants which could be achieved in one step via ring-opening and skeletal reconstruction reactions. Both the mechanisms and the applications of the corresponding products in organic and medicinal chemistry are also described.

Hyperoside suppresses osteoclasts differentiation and function through downregulating TRAF6/p38 MAPK signaling pathway.

Hyperoside (HP), as a natural product, can promote proliferation and differentiation of osteoblasts and presents a protective effect on ovariectomized (OVX) mice. However, the inhibitory effect of HP on osteoclasts (OCs) and the potential mechanism remain to be elucidated. In this study, it was found that HP could effectively inhibit the differentiation and bone resorption of OCs, and its intrinsic molecular mechanism was related to the inhibition of TRAF6/p38 MAPK signaling pathway. Therefore, HP could be a promising natural compound for lytic bone diseases.

Chemically Stable Guanidinium Covalent Organic Framework for the Efficient Capture of Low-Concentration Iodine at High Temperatures.

The capture of radioactive I2 vapor from nuclear waste under industrial operating conditions remains a challenging task, as the practical industrial conditions of high temperature (≥150 °C) and low I2 concentration (∼150 ppmv) are unfavorable for I2 adsorption. We report a novel guanidinium-based covalent organic framework (COF), termed TGDM, which can efficiently capture I2 under industrial operating conditions. At 150 °C and 150 ppmv I2, TGDM exhibits an I2 uptake of ∼30 wt %, which is significantly higher than that of the industrial silver-based adsorbents such as Ag@MOR (17 wt %) currently used in the nuclear fuel reprocessing industry. Characterization and theoretical calculations indicate that among the multiple types of adsorption sites in TGDM, only ionic sites can bond to I2 through strong Coulomb interactions under harsh conditions. The abundant ionic groups of TGDM account for its superior I2 capture performance compared to various benchmark adsorbents. In addition, TGDM exhibits exceptionally high chemical and thermal stabilities that fully meet the requirements of practical radioactive I2 capture (high-temperature, humid, and acidic environment) and differentiate it from other ionic COFs. Furthermore, TGDM has excellent recyclability and low cost, which are unavailable for the current industrial silver-based adsorbents. These advantages make TGDM a promising candidate for capturing I2 vapor during nuclear fuel reprocessing. This strategy of incorporating chemically stable ionic guanidine moieties in COF would stimulate the development of new adsorbents for I2 capture and related applications.

Installation of synergistic binding sites onto porous organic polymers for efficient removal of perfluorooctanoic acid.

Herein, we report a strategy to construct highly efficient perfluorooctanoic acid (PFOA) adsorbents by installing synergistic electrostatic/hydrophobic sites onto porous organic polymers (POPs). The constructed model material of PAF-1-NDMB (NDMB = N,N-dimethyl-butylamine) demonstrates an exceptionally high PFOA uptake capacity over 2000 mg g-1, which is 14.8 times enhancement compared with its parent material of PAF-1. And it is 32.0 and 24.1 times higher than benchmark materials of DFB-CDP (ß-cyclodextrin (ß-CD)-based polymer network) and activated carbon under the same conditions. Furthermore, PAF-1-NDMB exhibits the highest k2 value of 24,000 g mg-1 h-1 among all reported PFOA sorbents. And it can remove 99.99% PFOA from 1000 ppb to <70 ppt within 2 min, which is lower than the advisory level of Environmental Protection Agency of United States. This work thus not only provides a generic approach for constructing PFOA adsorbents, but also develops POPs as a platform for PFOA capture.

Ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromone synthons: catalyst-free access to skeletally-diverse 2-pyridone and optically active imidazoline derivatives.

Herein is reported the first example of ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromones 1 as versatile synthons, which can react with ammonia or primary aliphatic amines as binucleophiles, for the eco-friendly and atom-economical synthesis of diverse and functionalized 2-pyridones 3 with potential biological activity in good to excellent yields (77-93%). When using optically active 1,2-diphenylethylenediamine 2 as the binucleophile, the in situ generated 2-pyridone intermediates are successfully transformed to novel optically active functionalized imidazoline derivatives 4 with high efficiency (up to 87% yield). In particular, this is the first report on the catalyst-free intramolecular cyclization occurring between an amide and a primary aliphatic amine for the construction of imidazoline molecules.

Asymmetric construction of six vicinal stereogenic centers on hexahydroxanthones via organocatalytic one-pot reactions.

Inspired by the chemistry and biology of hexahydroxanthones, herein we report an organocatalytic Michael-Michael-Aldol-decarboxylation reaction that provides efficient access to biologically interesting fully substituted hexahydroxanthones bearing six contiguous stereogenic centers from readily accessible materials in acceptable yields (up to 63%) and excellent stereoselectivities (up to 10 : 1 dr and >99% ee). In other words, the reaction efficiently produces three chemical bonds and up to six vicinal stereogenic centers in a one-pot operation. In particular, to our knowledge, this is an asymmetric organocatalytic strategy enabling the first construction of six vicinal stereogenic centers on non-spirocyclic hexahydroxanthone frameworks.

Synthesis of methanesulfone-containing tetrasubstituted carbon stereocenters.

A methanesulfonylation reaction for the synthesis of sulfone-containing tetrasubstituted carbon stereocenters is described for the first time by simple treatment of indanedione-chromanone synthons with Et3N and easily accessible MsCl without any use of organometallic chemistry. This technology gave the corresponding valuable chromone-based 2-methanesulfonylated 1,3-indanediones in good yields (up to 89% yield) under mild conditions. The present work provides an attractive strategy for the construction of biologically interesting sulfone-containing tetrasubstituted carbon stereocenters, which might be valuable in medicinal chemistry.

Assembly of functionalized π-extended indolizine polycycles through dearomative [3+2] cycloaddition/oxidative decarbonylation.

Reported herein is an unexpected construction of functionalized π-extended indolizine polycycles through a one-pot two-step cascade process comprising the base-promoted dearomative [3+2] cycloaddition of quinilinium salts and 3-alkenyl oxindoles, followed by a DDQ-mediated oxidative decarbonylation. Moreover, we could achieve the substrate-controlled diverse synthesis of structurally strained cyclopropane spirooxindole by using pyridinium salts as starting materials.

Transition-metal-free cascade benzannulations for synthesizing 2-hydroxybenzophenones.

A set of cascade benzannulations of readily accessible chromone-3-carboxaldehydes and γ-nitroaldehydes for synthesizing biologically relevant 2-hydroxybenzophenones has been developed. The cascade was found to provide a transition-metal-free strategy for synthesizing 2-hydroxybenzophenones in acceptable yields (up to 57%).

Study on antitumor activities of the chrysin-chromene-spirooxindole on Lewis lung carcinoma C57BL/6 mice in vivo.

The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3, and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs.

Regioselective synthesis and evaluation of 2-amino 3-cyano chromene-chrysin hybrids as potential anticancer agents.

The first example of Ca(OH)2-activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K562 cells (IC50 = 6.41 µM). Furthermore, compound 3h induced apoptosis of K562 cells in a concentration-dependent manner, as well as induced the apoptosis possibly through promoting the formation of apoptotic DNA of cancer cell via the intrinsic apoptotic pathway. Thus, our results provide in vitro evidence that compound 3h may be a potential candidate for the development of new anti-tumour drugs.