Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists.

STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2'3'-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2'3'-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections.

Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors.

Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 µΜ of compound 6p or 6q combined with 2 µg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.

A new alkaloid and two organic acids from Portulaca oleracea L. and their bioactivities.

A new alkaloid, identified as 1-benzyl-2-nitroso-1,2,3,4-tetrahydroisoquinoline-6,7-diol, named oleraisoquinoline (1), and five organic acids and two esters, identified as 5-(hydroxymethyl)furan-2-carboxylic acid (2), 1H-pyrrole-2,5-dicarboxylic acid (3), (7E,10E)-octadeca-7,10-dienoic acid (4), (10E,13E)-octadeca-10,13-dienoic acid (5), (7E,10E)-hexadeca-7,10-dienoic acid (6), methyl tridecanoate (7) and methyl (9E,12E)-octadeca-9,12-dienoate (8), were isolated from Portulaca oleracea L., among which compounds 2 and 4‒7 were isolated for the first time. Moreover, the anti-inflammatory activities of compounds 1‒3 were studied, especially, compound 1 presented good inhibitory effects on the production of inflammatory factors IL-1ß and TNF-α.

Assessing China's development zones and carbon emissions.

The present article evaluates establishment of development zones and its association with carbon emissions. In the process of industrialization, carbon emissions in underdeveloped regions of the world increase with economic growth. In order to promote economic growth in the western region and strengthen the management of enterprise pollution emissions, the Chinese government has set up hundreds of development zones. Existing research shows that development zone establishment can promote economic growth; however, literature is scarce when the relationship is tested across region. Based on the panel data of five provinces with relatively backward economy in western China from 2001 to 2017, this paper constructs a "multi-period difference-in-difference" (DID) model with the establishment of development zones as a "quasi-natural experiment" to test the relationship. Findings reveal that development zone establishment increases carbon emissions in the region, and has a significant inhibitory effect on carbon emissions at national level. The conclusions of this paper provide empirical evidence and policy implications for reducing carbon emissions in economically underdeveloped areas.

A novel skeleton alkaloid from Portulaca oleracea L. and its bioactivities.

A novel skeleton alkaloid was obtained from Portulaca oleracea L., which was identified as 10,11-dihydroxybenzo[5',6'] pentaleno[1',2':3,4]pyrrolo[2,1-b]oxazol-7(11bH)-one, named oleracone M, and its structure was determined using UHPLC-ESI-QTOF/MS, 1D NMR and 2D NMR spectroscopy, and circular dichroism. Then the bioactivities of the compound were investigated including the anti-inflammatory, anti-acetylcholinesterase and antioxidant activities. The results showed that the novel skeleton alkaloid exhibited the potent effect on inhibiting the secretion of IL-1ß at 10 µM, anticholinesterase activity with IC50 value of 49.58 µM, and antioxidant activity with IC50 value of 66.43 µM.

Two novel amide alkaloids from Portulaca oleracea L. and their anti-inflammatory activities.

In this article, two novel amide alkaloids were identified as (E)-3-(4-hydroxy-3-methoxyphenyl)-1-(5-hydroxy-6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indol-1-yl)prop-2-en-1-one (1) and (E)-1-(5-hydroxy-6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indol-1-yl)-3-(4-hydroxyphenyl)prop-2-en-1-one (2), the two compounds were named oleraindole E and oleraindole F, respectively. The structures were elucidated using 1D and 2D NMR and HR-ESI-TOF-MS spectra. Additionally, the anti-inflammatory activities were evaluated on RAW264.7 cells induced by LPS, compounds 1 and 2 exhibited anti-inflammatory activities at 20 µM.

Seven compounds from Portulaca oleracea L. and their anticholinesterase activities.

A novel lignan, identified as 4-(3,4-dihydroxyphenyl)-6,7-dimethoxy-3a,4-dihydronaphtho[2,3-c]furan-1(3H)-one, named oleralignan A (1), together with six known compounds, loliolide (2), isololiolide (3), dehydrololiolide (4), daphnetin (5), esculetin (6), and trans-coumaric acid methyl ester (7) was obtained from Portulaca oleracea L., while compounds 3, 4, 6, and 7 were isolated from the plant for the first time. Their structures were elucidated using spectroscopic methods, including one- and two-dimensional NMR and high-resolution electrospray ionization time-of-flight mass spectrometry. In addition, the results of activity assay demonstrated that compounds 1-7 have anticholinesterase activities.