Synthesis of 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinones through a cyclized dearomatization and trichloromethylation cascade strategy.

A variety of 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinones were prepared in moderate to good yields with high regioselectivity through intramolecular 6-endo-dig cyclization and trichloromethylation of N3-alkynyl-2-pyridinyl-tethered quinazolinones in chloroform. Mechanistic studies revealed that chloroform might serve as a trichloromethyl anion precursor. Furthermore, the reaction could be easily performed on gram scales and an estrone-derived 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinone was prepared over five steps. The present method features broad substrate scope, good functional group tolerance, new dearomatization of pyridine rings, and chloroform as the trichloromethylation reagent.

Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity.

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

Potent Zinc(II)-Based Immunogenic Cell Death Inducer Triggered by ROS-Mediated ERS and Mitochondrial Ca2+ Overload.

Zn1 and Zn2 are Zn-based complexes that activate the immunogenic cell death (ICD) effect by Ca2+-mediated endoplasmic reticulum stress (ERS) and mitochondrial dysfunction. Compared with Zn1, Zn2 effectively caused reactive oxidative species (ROS) overproduction in the early phase, leading to ERS response. Severe ERS caused the release of Ca2+ from ER to cytoplasm and further to mitochondria. Excessive Ca2+ in mitochondria triggered mitochondrial dysfunction. The damage-associated molecular patterns (DAMPs) of CRT, HMGB1, and ATP occurred in T-24 cells exposed to Zn1 and Zn2. The vaccination assay demonstrated that Zn1 and Zn2 efficiently suppressed the growth of distant tumors. The elevated CD8+ cytotoxic T cells and decreased Foxp3+ cells in vaccinated mice supported our conclusion. Moreover, Zn1 and Zn2 improved the survival rate of mice compared with oxaliplatin. Collectively, our findings provided a new design strategy for a zinc-based ICD inducer via ROS-induced ERS and mitochondrial Ca2+ overload.

Physiological Function of RDL1 and RDL2 Subunits of the Ionotropic GABA Receptor in the Spodoptera litura with the CRISPR/Cas9 System In Vivo.

In insect ionotropic γ-aminobutyric acid receptor (iGABAR) subunits, only resistance to dieldrin (RDL) can be individually and functionally expressed in vitro. In lepidopteran, two to three RDL subtypes are identified; however, their physiological roles have not been distinguished in vivo. In this study, SlRdl1 and SlRdl2 of S. litura were individually knocked out using CRISPR/Cas9, respectively. The mortality and larval and pupal duration of KOSlRdl1 and KOSlRdl2 were increased. The flight time and distance were increased by 43.30%-80.66% and 58.96%-198.22%, respectively, in KOSlRdl1. The GABA-induced current was significantly decreased by 53.57%-74.28% and 46.91%-63.34% in the ventral nerve cord, and the GABA titer was significantly reduced by 17.65%-28.05% and 19.85%-42.46% in KOSlRdl1 and KOSlRdl2, respectively. In conclusion, SlRdl1 and SlRdl2 are necessary for the transmission of GABA-induced neural signals; however, only SlRdl1 could regulate the flight capability of S. litura. Our results provided a new avenue to study lepidopteran iGABARs.

Design and synthesis of pseudo-rutaecarpines as potent anti-inflammatory agents via regulating MAPK/NF-κB pathways to relieve inflammation-induced acute liver injury in mice.

Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1ß and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation.

Evolution of China regulatory guidance on the clinical evaluation of medical devices and its implication on pre-market and post-approval clinical evaluation strategies.

INTRODUCTION: The rapid growth of the medical device industry has driven the evolution of regulatory guidance on medical device clinical evaluation (MDCE) of the China National Medical Products Administration (NMPA), which consequently influences pre-market and post-approval clinical evaluation (CE) strategies. AREAS COVERED: We aimed to investigate the 3-stage evolution of NMPA regulatory guidance on MDCE (1. The era before specific CE guidance, 2. 2015 CE Guidance, and 3. 2021 CE Guidance Series), analyze the gaps between each stage, and assess the evolution's impact on pre-market and post-approval CE strategies. EXPERT OPINION: The fundamental principles of the NMPA 2021 CE Guidance Series were transformed from the 2019 International Medical Device Regulatory Forum documents. Compared with the 2015 guidance, the 2021 CE Guidance Series further clarifies the CE definition by emphasizing the ongoing activity of CE through an entire product lifecycle and the use of scientifically sound methods for CE and narrows the pre-market CE pathways into the equivalent device and clinical trial pathways. The 2021 CE Guidance Series simplifies the process for selecting the pre-market CE strategy but does not specify post-approval CE update cadency and general requirements for post-market clinical follow-up.

Regulatory requirements and optimization of multiple criteria decision analysis to quantify the benefit-risk assessment of medical devices.

INTRODUCTION: Worldwide medical device regulatory authorities increasingly rely on the benefit-risk ratio for decision-making. However, current benefit-risk assessment (BRA) methods are mostly descriptive, not quantitative. AREAS COVERED: We aimed to summarize the regulatory requirements of BRA, discuss the feasibility of adopting multiple criteria decision analysis (MCDA), and explore factors for optimizing the MCDA for quantitative BRA of devices. EXPERT OPINION: Regulatory organizations emphasize BRA in their guidance, and some recommend user-friendly worksheets to conduct qualitative/descriptive BRA. The MCDA is considered one of the most useful and relevant quantitative BRA methods by pharmaceutical regulatory agencies and the industry; the International Society for Pharmacoeconomics and Outcomes Research summarized the principles and good practice guidance of MCDA. We recommend optimizing the MCDA by considering the following unique characteristics of the device BRA: using data from state of the art as a control and clinical data from post-market surveillance and literature; considering the device's diverse characteristics when selecting controls; assigning weight according to type, magnitude/severity, and duration of benefits and risks; and including physician and patient opinions in the MCDA. This article is the first to explore using MCDA for device BRA and might lead to a novel quantitative BRA method for devices.

Worldwide regulatory organizations for medical devices emphasize benefit­risk assessment (BRA) in their guidance and recommend qualitative or descriptive BRA approaches. However, no guidance has described any quantitative BRA method for medical devices. The multiple criteria decision analysis (MCDA) method is considered the most useful and relevant quantitative BRA method for drugs by pharmaceutical regulatory agencies and industries. The principles of MCDA are described by the International Society for Pharmacoeconomics and Outcomes Research and lead to emerging good practice guidance on the implementation of MCDA to support healthcare decision-making. To optimize the MCDA method for the quantitative BRA of medical devices, we recommend considering the unique characteristics thereof; including using data from SOTA as a control; using additional clinical data from post-market surveillance and literature; considering the device's diverse characteristics when selecting a control; assigning weight according to the type, magnitude/severity, and duration of benefits and risks; and including both physician and patient opinions in the MCDA method. The medical device industry and device regulatory organizations could benefit from this article. A quantitative BRA tool can be developed based on our findings and can be used by agencies and companies to monitor the safety and effectiveness of medical devices throughout their life cycle. Future research should focus on developing these theoretical considerations into a user-friendly tool for the quantitative BRA of devices and the validation of such tools using different types of devices.

Fluoropolymer: A Review on Its Emulsion Preparation and Wettability to Solid-Liquid Interface.

In the preparation of a superamphiphobic surface, the most basic method is to reduce the surface free energy of the interface. The C-F bond has a very low surface free energy, which can significantly change the wettability of the solid-liquid interface and make it a hydrophobic or oleophobic, or even superamphiphobic surface. Based on the analysis of a large number of research articles, the preparation and application progress in fluoropolymer emulsion were summarized. After that, some corresponding thoughts were put forward combined with our professional characteristics. According to recent research, the status of the fluoropolymer emulsion preparation system was analyzed. In addition, all related aspects of fluoropolymer emulsion were systematically classified in varying degrees. Furthermore, the interaction between fluoropolymer structure and properties, especially the interaction with nanomaterials, was also explored. The aim of this review is to try to attract more scholars' attention to fluorocarbon interfacial materials. It is expected that it will make a certain theoretical and practical significance in the preparation and application of fluoropolymer.

Synthesis of 1,2,4-Oxadiazolines through Deoxygenative Cyclization of N-Vinyl-α,ß-Unsaturated Nitrones with in Situ Generated Nitrile Oxides from Hydroxamoyl Chlorides.

A variety of 1,2,4-oxadiazoline derivatives were synthesized in moderate to good yields through a deoxygenative cyclization cascade reaction of N-vinyl-α,ß-unsaturated nitrones and hydroxamoyl chlorides. Mechanistic studies revealed that the reaction underwent double additions of nitrile oxides to N-vinyl-α,ß-unsaturated nitrones, sequential elimination, and intramolecular cyclization to afford 1,2,4-oxadiazolines. Alternatively, 1,2,5-oxadiazolines were also obtained as major products in i-PrOH solvent through [3 + 3] cycloaddition and selective [3,3]-rearrangement. Moreover, the prepared 1,2,4-oxadiazolines were easily converted to polysubstituted pyrroles under thermal conditions.

Recent advances in the synthesis of 2,3-fused quinazolinones.

As one of the most important structural units in pharmaceuticals and medicinal chemistry, quinazolinone and its derivatives exhibit a wide range of biological and pharmacological activities, including anti-inflammatory, antitubercular, antiviral, and anticancer activities, etc. In particular, 2,3-fused quinazolinones have attracted much attention because the rings fused to the 2,3-positions of quinazolinones improve their rigidity and planarity. Their synthetic strategies have made great advances in recent years. Therefore, this review focuses on novel strategies for the synthesis of 2,3-fused quinazolinone derivatives from 2017 to 2022, such as the difunctionalization of alkenes, the ring-opening of easily available small rings, dehydrogenative cross-coupling reactions, transition-metal catalyzed cyclizations, cycloadditions, and other cascade reactions.

Synthesis of spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones through gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered indoles.

A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.

Cepharanthine hydrochloride inhibits the Wnt/ß­catenin/Hedgehog signaling axis in liver cancer.

Cepharanthine, a biscoclaurine alkaloid isolated from the roots of Stephania cephalantha Hayata, has been reported to demonstrate antitumor activity across multiple cancer types; however, the mechanisms are still under investigation. High transcriptional responses by both the Hedgehog and Wnt pathways are frequently associated with specific human cancers, including liver cancer. To investigate whether these signaling pathways are involved in the pharmaceutical action of cepharanthine, we investigated Hedgehog and Wnt signaling in models of liver cancer treated with a semi­synthetic cepharanthine derivative, cepharanthine hydrochloride (CH), in vitro and in vivo. By using MTT cytotoxic, scratch, Transwell, colony formation and flow cytometry assays, the pharmaceutical effect of CH was assessed. The compound was found to inhibit cellular proliferation and invasion, and promote apoptosis. Subsequent mechanistic investigations revealed that CH suppressed the Hedgehog/Gli1 signaling pathway by inhibiting Gli1 transcription and its transcriptional activity. CH also inhibited Wnt/ß­catenin signaling, and the pathway was found to be an upstream regulator of Hedgehog signaling in CH­treated liver cancer cells. Finally, the antitumor effects of CH were demonstrated in an in vivo xenograft tumor model. Immunohistochemical analysis indicated that Gli1 protein levels were diminished in CH­treated xenografts, compared with that noted in the controls. In summary, our results highlight a novel pharmaceutical antitumor mechanism of cepharanthine and provide support for CH as a clinical therapy for refractory liver cancer and other Wnt/Hedgehog­driven cancers.

One-pot synthesis of oxoaporphines as potent antitumor agents and investigation of their mechanisms of actions.

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, 4B displayed the most potent activity with an IC50 value of 0.5 µM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that 4 and 4B induced cell cycle arrest at G2/M phase; in contrast, 4V induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds 4, 4B and 4V, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound 4B effectively inhibited tumor growth in a mouse xenograft model bearing T-24.

Sublethal doses of broflanilide prevents molting in the fall armyworm, Spodoptera frugiperda via altering molting hormone biosynthesis.

Broflanilide is a novel insecticide with a unique mode of action on the insect GABA receptor and is registered worldwide for the control of agricultural pests. It shows high efficacy in controlling the fall armyworm (FAW) Spodoptera frugiperda, which is a destructive pest to various crops. FAW was exposed to sublethal concentrations of broflanilide to determine its impact on insect development. Sublethal doses (LD10 and LD30) caused failure of ecdysis, reduced body length of larvae, malformation of pupae, and vestigial wing formation in adults. Also, broflanilide at LD30 significantly reduced the amount of molting hormone (MH). After exposure to LD10 or LD30 broflanilide, expression of five Halloween genes, which participate in MH biosynthesis, were found to be altered. Specifically, the transcript levels of SfrCYP307A1 (Spook), SfrCYP314A1 (Shade) and SfrCYP315A1 (Shadow) in 3rd day larvae were significantly decreased as well as SfrCYP302A1 (Disembodied) and SfrCYP306A1 (Phantom) in 5th day pupae. In contrast, the transcript levels of SfrCYP302A1 in 3rd day larvae, SfrCYP307A1 and SfrCYP314A1 in 5th day pupae, and SfrCYP306A1, SfrCYP307A1 and SfrCYP315A1 in 0.5th day adults were significantly increased. Our results demonstrate that broflanilide caused the failure of ecdysis in FAW possibly by influencing the intake of cholesterol through inhibition of feeding and also via altering expression of genes important for MH biosynthesis.

microRNA-10a-5p overexpression suppresses malignancy of colon cancer by regulating human liver cancer fibroblasts.

The crosstalk between tumor and stroma plays a critical role in cancer metastasis. However, the function of miR-10a-5p on liver fibroblasts in the metastatic microenvironment of colon cancer (CC) and the effect of activated fibroblasts on CC cells are still unclear. In our study, miR-10a-5p overexpression inhibited the proliferation, migration, and IL-6/IL-8 level of LX-2 cells and human liver cancer fibroblasts (HLCFs). Moreover, miR-10a-5p had lower expression in HLCFs than in human liver normal fibroblasts (HLNFs). The conditioned medium (CM) from LX-2 cells with miR-10a-5p overexpression or HLNFs could inhibit the invasion, migration, and stemness of CC SW480 cells, whereas HLCFs CM could promote these malignant phenotypes of SW480 cells. The present study illustrates the effect of miR-10a-5p on the liver fibroblasts and the altered liver fibroblasts in the microenvironment on CC cells induced by miR-10a-5p, which may aid the understanding of the mechanisms underlying CC liver metastasis.

Nickel(II)-Catalyzed [3 + 2] Cycloaddition of Nitrones and Allenoates to Access N-Vinylindoles and N-Vinylpyrroles.

A variety of N-vinylindoles and N-vinylpyrroles were prepared in moderate to good yields through the nickel(II)-catalyzed [3 + 2] cycloaddition of α,ß-unsaturated nitrones with allenoates under mild reaction conditions. A rational mechanism for the formation of N-vinylindoles was proposed based on the 18O-labeled experiments and key intermediates detected by high-resolution mass spectrometry trace experiments. The present method highlights a nickel(II)-controlled cyclization, atom-economical reaction, broad substrate scope, good functional group tolerance, and high Z-stereoselectivity for the enamine bond.

3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis.

Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.

Copper(I)-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides with bicyclic alkenes.

A variety of tetrahydroquinoline-fused bicycles bearing multiple stereocenters are prepared in good yields with high diastereoselectivity through Cu2O-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides (ao-QMs) with bicyclic alkenes. Mechanistic studies reveal that the Cu(i) catalyst not only promotes the formation of ao-QMs through a radical process by single electron transfer but also accelerates [4 + 2] cycloaddition. The reaction was easily performed on gram scale and the obtained tetrahydroquinoline-fused bicycles can be converted to diverse tetrahydroquinoline scaffolds.

[Industrial Emission Characteristics and Control Countermeasures of VOCs in Chinese Rapid Economic Development Areas].

With the rapid development of China's economy, volatile organic compounds (VOCs) as the precursor of smog and ozone are of increasing concern, especially in rapidly developing areas. This paper is a systematic analysis of VOCs emissions and distribution trends in 12 typical industrial sectors, garbage and wastewater treatment plants, comprehensive industrial parks, and residential districts in Beijing-Tianjin-Hebei, Yangtze River Delta, and Pearl River Delta Regions. The results show that pharmacy, rubber producing, as well as paint spraying are the top three industries among the 12 typical industries with the highest average VOCs emission concentrations at 541, 499, and 450 mg·m-3, respectively. By comparison, the average emission concentration of VOCs from the pharmaceutical industry in Yangtze River Delta and Beijing-Tianjin-Hebei Region was, respectively, about 112 and 1.00×103 mg·m-3. The paint spraying industry in the Pearl River Delta region has the highest emission rate with an average concentration of 1.04×103 mg·m-3. The investigation pertaining to the distribution of different VOCs categories indicates that highly toxic aromatics and halogenated hydrocarbons account for the highest emissions in paint spraying and pharmaceutical industries, reaching ratios of 55.99% and 26.57%, respectively. Additionally, among the three major economic zones, the VOCs concentration is the lowest in residential areas and comprehensive industrial parks in the Yangtze River Delta but the highest in the Beijing-Tianjin-Hebei Region, which is consistent with the distribution of industrial emissions in each region. Moreover, the research reveals that VOCs concentration in residential districts experienced a fluctuating reduction from 2002 to 2018. The significant reduction since 2016 suggests that formulated policies, laws and standards, along with the performed techniques have made significant contributions to the control of VOCs.

[VOCs Emission Inventory and Variation Characteristics of Artificial Sources in Hubei Province in the Yangtze River Economic Belt].

In this study, a 2018 anthropogenic volatile organic compounds (VOCs) emission inventory in Hubei Province was conducted using the emission factor method based on activity levels of five sources. The emission characteristics and variation trends of process sources from 2009 to 2018 were further analyzed. Total anthropogenic VOCs emissions were 6.52×105 tons in Hubei Province, accounting for about 6.41% of the country's total omissions. The contributions of fossil combustion sources, process sources, solvent sources, mobile sources, and waste disposal sources were 3.26%, 76.39%, 4.54%, 14.72%, and 1.09%, respectively. Process sources involving 45 sub-categories of nine industries accounted for a significant proportion of VOCs emissions, with Wuhan and Yichang recording the highest VOCs emission levels. The VOCs emissions intensity of each city and state were analyzed based the level of economic activity and territorial area. Tianmen and Shennongjia had higher VOCs emissions per unit of GDP, while Wuhan, Ezhou, and Tianmen had higher VOCs emissions per unit area. Regarding process source contributions, VOCs emissions increased progressively to 2.45×105 tons in 2009 and then stabilized between 2015 and 2017 with maximum emissions of 7.01×105 tons. In 2018, VOCs emissions decreased to 4.98×105 tons. This trend was similar to national anthropogenic emissions. Two industrial sectors, namely chemical raw materials and rubber and plastics, were the main driving force with contributions of 33.85%-51.55% and 7.07%-38.13%, respectively. Among them, the production of chemicals and active pesticide and pharmaceutical ingredients played an important role in contributing to VOCs emissions, while emissions during foam plastics production varied greatly, increasing sharply to more than 2.00×104 tons in 2015-2017. Under the guidance of the relevant national and local policies, emissions from key industries were significantly reduced in Hubei Province.