Ru(II)-Catalyzed Carboamination of Olefins with α-Carbonyl Sulfoxonium Ylides.

The first ruthenium-catalyzed carboamination of olefins with α-carbonyl sulfoxonium ylides is reported. The utilization of an inexpensive ruthenium catalyst enables the concise synthesis of pharmaceutically important isoindolin-1-ones, which possess both a stereogenic center and ß-carbonyl side chain. This method is mild, efficient, and scalable and allows for the coupling of a wide range of aryl-, heteroaryl-, alkenyl-, and alkyl-substituted sulfoxonium ylides. Moreover, the carbonyl side chain in the resulting product provides a good handle for downstream transformations. For mechanistic studies, a ruthacyle complex is obtained and proven to be the key intermediate in both catalytic and stoichiometric reactions.

Synthesis and evaluation of pentacyclic triterpenoids conjugates as novel HBV entry inhibitors targeting NTCP receptor.

Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.

Two New Sesquiterpenoids and a New Shikimic Acid Metabolite from Mangrove Sediment-Derived Fungus Roussoella sp. SCSIO 41427.

Two new sesquiterpenoid derivatives, elgonenes M (1) and N (2), and a new shikimic acid metabolite, methyl 5-O-acetyl-5-epi-shikimate (3), were isolated from the mangrove sediment-derived fungus Roussoella sp. SCSIO 41427 together with fourteen known compounds (4-17). The planar structures were elucidated through nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analyses. The relative configurations of 1-3 were ascertained by NOESY experiments, while their absolute configurations were determined by electronic circular dichroism (ECD) calculation. Elgonene M (1) exhibited inhibition of interleukin-1ß (IL-1ß) mRNA, a pro-inflammatory cytokine, at a concentration of 5 µM, with an inhibitory ratio of 31.14%. On the other hand, elgonene N (2) demonstrated inhibition at a concentration of 20 µM, with inhibitory ratios of 27.57%.

Discovery of Enzyme Inhibitors from Mangrove Sediment Derived Fungus Trichoderma harzianum SCSIO 41051.

One new fatty acid derivative, (2E,4E)-6,7-dihydroxy-2-methylocta-2,4-dienoic acid (1), and 16 known compounds (2-17) were isolated from the mangrove sediment derived fungus Trichoderma harzianum SCSIO 41051. Their structures were established by spectroscopic methods, computational ECD, and Mo2(OAc)4-induced ECD experiment. All the compounds were evaluated for their acetylcholinesterase (AChE) and pancreatic lipase (PL) inhibition. Compounds 9 and 14 exhibited moderate AChE inhibitory activities with IC50 values of 2.49 and 2.92 µM, respectively, which compounds 8 and 9 displayed moderate inhibition on PL with IC50 value of 2.30 and 2.34 µM, respectively.

Marine-Fungi-Derived Gliotoxin Promotes Autophagy to Suppress Mycobacteria tuberculosis Infection in Macrophage.

The Mycobacterium tuberculosis (MTB) infection causes tuberculosis (TB) and has been a long-standing public-health threat. It is urgent that we discover novel antitubercular agents to manage the increased incidence of multidrug-resistant (MDR) or extensively drug-resistant (XDR) strains of MTB and tackle the adverse effects of the first- and second-line antitubercular drugs. We previously found that gliotoxin (1), 12, 13-dihydroxy-fumitremorgin C (2), and helvolic acid (3) from the cultures of a deep-sea-derived fungus, Aspergillus sp. SCSIO Ind09F01, showed direct anti-TB effects. As macrophages represent the first line of the host defense system against a mycobacteria infection, here we showed that the gliotoxin exerted potent anti-tuberculosis effects in human THP-1-derived macrophages and mouse-macrophage-leukemia cell line RAW 264.7, using CFU assay and laser confocal scanning microscope analysis. Mechanistically, gliotoxin apparently increased the ratio of LC3-II/LC3-I and Atg5 expression, but did not influence macrophage polarization, IL-1ß, TNF-a, IL-10 production upon MTB infection, or ROS generation. Further study revealed that 3-MA could suppress gliotoxin-promoted autophagy and restore gliotoxin-inhibited MTB infection, indicating that gliotoxin-inhibited MTB infection can be treated through autophagy in macrophages. Therefore, we propose that marine fungi-derived gliotoxin holds the promise for the development of novel drugs for TB therapy.

Gancao Fuzi decoction regulates the Th17/Treg cell imbalance in rheumatoid arthritis by targeting Foxp3 via miR-34a.

ETHNOPHARMACOLOGICAL RELEVANCE: During the Eastern Han Dynasty, Zhang Zhongjing first recorded the Gancao Fuzi decoction (GCFZD) formula in the "Synopsis of the Golden Chamber", which is reportedly an effective and safe treatment for rheumatoid arthritis (RA). However, the mechanism underlying the observed improvement in the T helper 17 (Th17)/regulatory T (Treg) cell imbalance in RA obtained with GCFZD has not been reported. AIM OF THE STUDY: This study aimed to demonstrate whether GCFZD ameliorated RA by modulating the Th17/Treg imbalance in RA mice. MATERIALS AND METHODS: Collagen was used to induce a model of collagen-induced arthritis (CIA) in mice. GCFZD was administered by gavage, and the arthritis index score, imaging and histopathological changes of the ankle joints, and the levels of the immunoglobulin G (IgG) class antibodies and proinflammatory factors in serum were determined. In addition, the frequencies of Th17 and Treg cells, the levels of relevant transcription factors and functional factors and the miR-34a gene in the spleen and the levels of interleukin-17A (IL-17A) and IL-10 in serum were determined. RESULTS: GCFZD significantly reduced the arthritis score, improved joint swelling and bone damage, reduced the pathological score, and decreased the serum levels of IgG class antibody (IgG and IgG2a) and proinflammatory factor [tumour necrosis factor-alpha (TNF-α), IL-1ß and IL-6]. Moreover, the Th17-cell proportion, the expression level of the Th17-specific transcription factor retinoic acid-related orphan receptor γt (RORγt) and functional factor IL-17A in the spleen, and the serum IL-17A level were decreased, whereas the Treg cell proportion, expression levels of the Treg-specific transcription factor forkhead box P3 (Foxp3) and functional factor IL-10 in the spleen, and the serum IL-10 level were increased. Furthermore, GCFZD inhibited miR-34a gene expression while promoting Foxp3 protein expression. CONCLUSIONS: The findings of this study demonstrate the therapeutic effect of GCFZD on mice with CIA, and the mechanism is related to an improvement in the Th17/Treg cell imbalance by targeting Foxp3 via miR-34a.

Aromatic Acids and Leucine Derivatives Produced from the Deep-Sea Actinomycetes Streptomyceschumphonensis SCSIO15079 with Antihyperlipidemic Activities.

Six new aromatic acids (1-6) and three new leucine derivatives containing an unusual oxime moiety (7-9) were isolated and identified from the deep-sea-derived actinomycetes strain Streptomyces chumphonensis SCSIO15079, together with two known compounds (10-11). The structures of 1-9 including absolute configurations were determined by detailed NMR, MS, and experimental and calculated electronic circular dichroism spectroscopic analyses. Compounds 1-9 were evaluated for their antimicrobial and cytotoxicity activities, as well as their effects on intracellular lipid accumulation in HepG2 cells. Compounds 3 and 4, with the most potent inhibitory activity on intracellular lipid accumulation at 10 µM, were revealed with potential antihyperlipidemic effects, although the mechanism needs to be further studied.

Synthesis and antitumor activity of new tetrahydrocurcumin derivatives via click reaction.

Three new derivatives of tetrahydrocurcumin 6, 7 and 9 have been prepared as potent antitumor agents using copper(II)-catalyzed 'click chemistry'. Their structures were identified using 1H-NMR, 13C-NMR and HRMS techniques. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay has been carried out to investigate the in vitro cytotoxicity against human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2) and human colon carcinoma (HCT-116). Compound 6 has showed significant inhibitory activity against HCT-116 cell line with an IC50 value of 17.86 µM compared to tetrahydrocurcumin (50.96 µM) and positive control etoposide (19.48 µM) while showed no inhibitory activity against NCM460 cell line. Compounds 7 showed moderate inhibitory activity compared to tetrahydrocurcumin and etoposide while compound 9 showed no obvious inhibitory activity. The results suggested further structure modifications of tetrahydrocurcumin to improve its anticancer activity.[Formula: see text].

Engineered polymer nanoparticles incorporating l-amino acid groups as affinity reagents for fibrinogen.

Synthetic polymer hydrogel nanoparticles (NPs) were developed to function as abiotic affinity reagents for fibrinogen. These NPs were made using both temperature-sensitive N-isopropyl acrylamide (NIPAm) and l-amino acid monomers. Five kinds of l-amino acids were acryloylated to obtain functional monomers: l-phenylalanine (Phe) and l-leucine (Leu) with hydrophobic side chains, l-glutamic acid (Glu) with negative charges, and l-lysine (Lys) and l-arginine (Arg) with positive charges. After incubating the NPs with fibrinogen, γ-globulin, and human serum albumin (HSA) respectively, the NPs that incorporated N-acryloyl-Arg monomers (AArg@NPs) showed the strongest and most specific binding affinity to fibrinogen, when compared with γ-globulin and HSA. Additionally, the fibrinogen-AArg binding model had the best docking scores, and this may be due to the interaction of positively charged AArg@NPs and the negatively charged fibrinogen D domain and the hydrophobic interaction between them. The specific adsorption of AArg@NPs to fibrinogen was also confirmed by the immunoprecipitation assay, as the AArg@NPs selectively trapped the fibrinogen from a human plasma protein mixture. AArg@NPs had a strong selectivity for, and specificity to, fibrinogen and may be developed as a potential human fibrinogen-specific affinity reagent.

Engineered polymer nanoparticles incorporating L-amino acid groups as affinity reagents for fibrinogen / 药物分析学报

Synthetic polymer hydrogel nanoparticles(NPs)were developed to function as abiotic affinity reagents for fibrinogen.These NPs were made using both temperature-sensitive N-isopropyl acrylamide(NIPAm)and L-amino acid monomers.Five kinds of L-amino acids were acryloylated to obtain functional mono-mers:L-phenylalanine(Phe)and L-leucine(Leu)with hydrophobic side chains,L-glutamic acid(Glu)with negative charges,and L-lysine(Lys)and L-arginine(Arg)with positive charges.After incubating the NPs with fibrinogen,y-globulin,and human serum albumin(HSA)respectively,the NPs that incorporated N-acryloyl-Arg monomers(AArg@NPs)showed the strongest and most specific binding affinity to fibrin-ogen,when compared with y-globulin and HSA.Additionally,the fibrinogen-AArg binding model had the best docking scores,and this may be due to the interaction of positively charged AArg@NPs and the negatively charged fibrinogen D domain and the hydrophobic interaction between them.The specific adsorption of AArg@NPs to fibrinogen was also confirmed by the immunoprecipitation assay,as the AArg@NPs selectively trapped the fibrinogen from a human plasma protein mixture.AArg@NPs had a strong selectivity for,and specificity to,fibrinogen and may be developed as a potential human fibrinogen-specific affinity reagent.

Effects of Sodium Phosphate and Sodium Nitrite on the Pitting Corrosion Process of X70 Carbon Steel in Sodium Chloride Solution.

In this paper, effects of sodium phosphate (Na3PO4) and sodium nitrite (NaNO2) on the pitting corrosion of X70 carbon steel in 0.10 mol/L NaCl solution were investigated by potentiodynamic polarization technique, electrochemical impedance spectroscopy (EIS) method, scanning electron microscope (SEM) and scanning electrochemical microscope (SECM). The SECM equipment was used to observe the dynamic processes of the pitting corrosion in situ. Na3PO4 or NaNO2 in the sodium chloride solution decreased the local anodic dissolution and increased the pitting resistance of the specimen. By analysis and comparison, it can be concluded that the inhibition effect of Na3PO4 is mainly due to the formation of a salt film, while the corrosion inhibition of NaNO2 is principally attributed to a protective oxide film on the electrode surface.

Vinblastine-Loaded Nanoparticles with Enhanced Tumor-Targeting Efficiency and Decreasing Toxicity: Developed by One-Step Molecular Imprinting Process.

Molecularly imprinted polymers have exhibited good performance as carriers on drug loading and sustained release. In this paper, vinblastine (VBL)-loaded polymeric nanoparticles (VBL-NPs) were prepared by a one-step molecular imprinting process, avoiding the waste and incomplete removal of the template, and evaluated as targeting carriers for VBL delivery after modification. Using acryloyl amino acid comonomers and disulfide cross-linkers, VBL-NPs were synthesized and then conjugated with poly(ethylene glycol)-folate. The dynamic size of the obtained VBL-NPs-PEG-FA was 258.3 nm (PDI = 0.250), and the encapsulation efficiency was 45.82 ± 1.45%. The nanoparticles of VBL-NPs-PEG-FA were able to completely release VBL during 48 h under a mimic tumor intracellular condition (pH 4.5, 10 mM glutathione (GSH)), displaying significant redox responsiveness, whereas the release rates were much slower in the mimic body liquid (pH 7.4, 2 µM GSH) and tumor extracellular environment (pH 6.5, 2 µM GSH). Furthermore, the carriers NPs-PEG-FA, prepared without VBL, showed satisfactory intrinsic hemocompatibility, cellular compatibility, and tumor-targeting properties: they could rapidly and efficiently accumulate to folate receptor positive Hela cells and then internalized via receptor-mediated endocytosis, and the retention in tumor tissues could last for over 48 h. Interestingly, VBL-NPs-PEG-FA could evidently increase the accumulation of VBL in tumor tissues while decreasing the distribution of VBL in organs, exert similar anticancer efficacy against Hela tumors in the xenograft model of nude mice to VBL injection, and significantly improve the abnormality of liver and spleen observed in VBL injection. VBL-NPs-PEG-FA has the potential to be the delivery carrier for VBL by enhancing the tumor-targeting efficacy of VBL and decreasing toxicity to normal tissues.

Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors.

A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 µM and 0.86 µM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 µM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 µM, 32.7 µM and 12.3 µM respectively.

Molecularly imprinted nanoparticles and their releasing properties, bio-distribution as drug carriers.

Molecular imprinted nanoparticles (MINPs) can memorize the shape and functional group positions complementary to template, which account for the large drug loading capacity and slow drug release behavior as drug carriers. We synthesized MINPs via precipitation polymerization with vinblastine (VBL) as a model drug, and investigated the drug loading, releasing property in vitro and bio-distribution in vivo. The obtained MINPs, from 300 to 450 nm, had smooth surface and favorable dispersibility. The entrapment efficacy and drug loading capacity of VBL loaded MINPs (MINPs-VBL) were 83.25% and 8.72% respectively. In PBS (pH7.4), MINPs-VBL showed sustained release behavior. The cumulative release percentage reached about 70% during 216 h and no burst release was observed. The releasing behavior of MINPs-VBL in vitro conformed to the first-order kinetics model. MINPs-VBL and commercially available vinblastine sulfate injection (VBL injection) were injected via tail vein of SD rats respectively to investigate the bio-distribution. MINPs-VBL group showed higher concentration of VBL in tissues and serum than VBL injection group after 60 min, and the drug level in liver was the highest. MINPs-VBL exhibited liver targeting trend to some extent, which was based on the evaluation of drug targeting index (DTI) and drug selecting index (DSI).

Molecularly imprinted polymers on a silica surface for the adsorption of tobacco-specific nitrosamines in mainstream cigarette smoke.

Tobacco-specific nitrosamines are one of the most important groups of carcinogens in tobacco products. Using adsorbents as filter additives is an effective way to reduce tobacco-specific nitrosamines in cigarette smoke. Molecularly imprinted polymers (MIPs) using nicotinamide as template were grafted on the silica gel surface to obtain MIP@SiO2 and employed as filter additives to absorb tobacco-specific nitrosamines in mainstream cigarette smoke. Four milligrams of MIP@SiO2 per cigarette was added to the interface between filter and tobacco rod to prepare a binary filter system. The mainstream smoke was collected on an industry-standard Cambridge filter pad and extracted with ammonium acetate aqueous solution before analysis. Compared to the cigarette smoke of the control group, the levels of tobacco-specific nitrosamines with silica gel and with MIP@SiO2 were both reduced, and the adsorption rates of N-nitrosonornicotine, N-nitrosoanabasine, N-nitrosoanatabine, and 4-(methylnitrosamino)-1-(3-pyridine)-1-butanone with silica gel and with MIP@SiO2 were 20.76, 15.32, 18.79, and 18.01%, and 41.33, 34.04, 37.86, and 35.53%, respectively. Furthermore the content of total particle materials in cigarette smoke with silica gel was decreased evidently but showed no observable change with MIP@SiO2 . It indicated MIP@SiO2 could selectively reduce tobacco-specific nitrosamines in the mainstream cigarette smoke with no change to the cigarette flavor.