New Pyrroline Isolated from Antarctic Krill-Derived Actinomycetes Nocardiopsis sp. LX-1 Combining with Molecular Networking.

Antarctic krill (Euphausia superba) of the Euphausiidae family comprise one of the largest biomasses in the world and play a key role in the Antarctic marine ecosystem. However, the study of E. superba-derived microbes and their secondary metabolites has been limited. Chemical investigation of the secondary metabolites of the actinomycetes Nocardiopsis sp. LX-1 (in the family of Nocardiopsaceae), isolated from E. superba, combined with molecular networking, led to the identification of 16 compounds a-p (purple nodes in the molecular network) and the isolation of one new pyrroline, nocarpyrroline A (1), along with 11 known compounds 2-12. The structure of the new compound 1 was elucidated by extensive spectroscopic investigation. Compound 2 exhibited broad-spectrum antibacterial activities against A. hydrophila, D. chrysanthemi, C. terrigena, X. citri pv. malvacearum and antifungal activity against C. albicans in a conventional broth dilution assay. The positive control was ciprofloxacin with the MIC values of <0.024 µM, 0.39 µM, 0.39 µM, 0.39 µM, and 0.20 µM, respectively. Compound 1 and compounds 7, 10, and 11 displayed antifungal activities against F. fujikuroi and D. citri, respectively, in modified agar diffusion test. Prochloraz was used as positive control and showed the inhibition zone radius of 17 mm and 15 mm against F. fujikuroi and D. citri, respectively. All the annotated compounds a-p by molecular networking were first discovered from the genus Nocardiopsis. Nocarpyrroline A (1) features an unprecedented 4,5-dihydro-pyrrole-2-carbonitrile substructure, and it is the first pyrroline isolated from the genus Nocardiopsis. This study further demonstrated the guiding significance of molecular networking in the research of microbial secondary metabolites.

Bioactivity-Guided Screening of Antimicrobial Secondary Metabolites from Antarctic Cultivable Fungus Acrostalagmus luteoalbus CH-6 Combined with Molecular Networking.

With the increasingly serious antimicrobial resistance, discovering novel antibiotics has grown impendency. The Antarctic abundant microbial resources, especially fungi, can produce unique bioactive compounds for adapting to the hostile environment. In this study, three Antarctic fungi, Chrysosporium sp. HSXSD-11-1, Cladosporium sp. HSXSD-12 and Acrostalagmus luteoalbus CH-6, were found to have the potential to produce antimicrobial compounds. Furthermore, the crude extracts of CH-6 displayed the strongest antimicrobial activities with 72.3-84.8% growth inhibition against C. albicans and Aeromonas salmonicida. The secondary metabolites of CH-6 were researched by bioactivity tracking combined with molecular networking and led to the isolation of two new α-pyrones, acrostalapyrones A (1) and B (2), along with one known analog (3), and three known indole diketopiperazines (4-6). The absolute configurations of 1 and 2 were identified through modified Mosher's method. Compounds 4 and 6 showed strong antimicrobial activities. Remarkably, the antibacterial activity of 6 against A. salmonicida displayed two times higher than that of the positive drug Ciprofloxacin. This is the first report to discover α-pyrones from the genus Acrostalagmus, and the significant antimicrobial activities of 4 and 6 against C. albicans and A. salmonicida. This study further demonstrates the great potential of Antarctic fungi in the development of new compounds and antibiotics.

Self-developed NF-κB inhibitor 270 protects against LPS-induced acute kidney injury and lung injury through improving inflammation.

Sepsis-induced acute kidney injury (AKI) and acute lung injury (ALI) have high morbidity and mortality, with no effective clinically available drugs. Anti-inflammation is effective strategy in the therapy of AKI and ALI. NF-κB is a target for the development of anti­inflammatory agents. The purpose of the study is to evaluate the effect of 270, self-developed NF-κB inhibitor, in LPS-induced AKI and ALI. LPS-induced macrophages were used to examine the anti-inflammation activity of 270 in vitro. Sepsis-induced AKI and ALI mice models were established by intraperitoneal injection of LPS (10 mg/kg) for 24 h. Oral administration 270 for 14 days before LPS stimulation. Plasma, kidney and lung tissues were collected and used for histopathology, biochemical assay, ELISA, RT-PCR, and western blot analyses. In vitro, we showed that 270 suppressed the inflammation response in LPS-induced RAW 264.7 macrophages and bone marrow derived macrophages. In vivo, we found that 270 ameliorated LPS-induced AKI and ALI, as evidenced by improving various pathological changes, reducing the expression of pro-inflammation genes, blocking the activation of NF-κB and JNK pathways, attenuating the elevated myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, ameliorating the activated ER stress, reversing the inhibition effect on autophagy in kidney and lung tissues, and alleviating the enhanced plasma level of creatinine (Crea), blood urea nitrogen (BUN) and pro-inflammation cytokines. Our investigations provides evidence that NF-κB inhibitor 270 is a potential drug that against LPS-induced AKI and ALI in the future.

Sesquiterpenoids From the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The fungal strains Pseudogymnoascus are a kind of psychrophilic pathogenic fungi that are ubiquitously distributed in Antarctica, while the studies of their secondary metabolites are infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of six new tremulane sesquiterpenoids pseudotremulanes A-F (1-6), combined with one known analog 11,12-epoxy-12ß-hydroxy-1-tremulen-5-one (7), and five known steroids (8-12). The absolute configurations of the new compounds (1-6) were elucidated by their ECD spectra and ECD calculations. Compounds 1-7 were proved to be isomeride structures with the same chemical formula. Compounds 1/2, 3/4, 1/4, and 2/3 were identified as four pairs of epimerides at the locations of C-3, C-3, C-9, and C-9, respectively. Compounds 8 and 9 exhibited cytotoxic activities against human breast cancer (MDA-MB-231), colorectal cancer (HCT116), and hepatoma (HepG2) cell lines. Compounds 9 and 10 also showed antibacterial activities against marine fouling bacteria Aeromonas salmonicida. This is the first time to find terpenoids and steroids in the fungal genus Pseudogymnoascus.

Nitrogenous Compounds from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus which is ubiquitously distributed in Antarctica. While the studies of its secondary metabolites are infrequent. Systematic research of the metabolites of the Antarctic fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of one new pyridine derivative, 4-(2-methoxycarbonyl-ethyl)-pyridine-2-carboxylic acid methyl ester (1), together with one pyrimidine, thymine (2), and eight diketopiperazines, cyclo-(dehydroAla-l-Val) (3), cyclo-(dehydroAla-l-Ile) (4), cyclo-(dehydroAla-l-Leu) (5), cyclo-(dehydroAla-l-Phe) (6), cyclo-(l-Val-l-Phe) (7), cyclo-(l-Leu-l-Phe) (8), cyclo-(l-Trp-l-Ile) (9) and cyclo-(l-Trp-l-Phe) (10). The structures of these compounds were established by extensive spectroscopic investigation, as well as by detailed comparison with literature data. This is the first report to discover pyridine, pyrimidine and diketopiperazines from the genus of Pseudogymnoascus.

New Polyketides from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus with a ubiquitous distribution in Antarctica. Meanwhile, the study of its secondary metabolites is infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11, guided by the method of molecular networking, led to the isolation of one novel polyketide, pseudophenone A (1), along with six known analogs (2-7). The structure of the new compound was elucidated by extensive spectroscopic investigation and single-crystal X-ray diffraction. Pseudophenone A (1) is a dimer of diphenyl ketone and diphenyl ether, and there is only one analog of 1 to the best of our knowledge. Compounds 1 and 2 exhibited antibacterial activities against a panel of strains. This is the first time to use molecular networking to study the metabolic profiles of Antarctica fungi.

Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors.

A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.

Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.

A Novel Bromophenol Derivative BOS-102 Induces Cell Cycle Arrest and Apoptosis in Human A549 Lung Cancer Cells via ROS-Mediated PI3K/Akt and the MAPK Signaling Pathway.

Bromophenol is a type of natural marine product. It has excellent biological activities, especially anticancer activities. In our study of searching for potent anticancer drugs, a novel bromophenol derivative containing indolin-2-one moiety, 3-(4-(3-([1,4'-bipiperidin]-1'-yl)propoxy)-3-bromo-5-methoxybenzylidene)-N-(4-bromophenyl)-2-oxoindoline-5-sulfonamide (BOS-102) was synthesized, which showed excellent anticancer activities on human lung cancer cell lines. A study of the mechanisms indicated that BOS-102 could significantly block cell proliferation in human A549 lung cancer cells and effectively induce G0/G1 cell cycle arrest via targeting cyclin D1 and cyclin-dependent kinase 4 (CDK4). BOS-102 could also induce apoptosis, including activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP, ΔΨm), and leading cytochrome c release from mitochondria. Further research revealed that BOS-102 deactivated the PI3K/Akt pathway and activated the mitogen-activated protein kinase (MAPK) signaling pathway resulting in apoptosis and cell cycle arrest, which indicated that BOS-102 has the potential to develop into an anticancer drug.

Discovery of Novel Bromophenol Hybrids as Potential Anticancer Agents through the Ros-Mediated Apoptotic Pathway: Design, Synthesis and Biological Evaluation.

A series of bromophenol hybrids with N-containing heterocyclic moieties were designed, and their anticancer activities against a panel of five human cancer cell lines (A549, Bel7402, HepG2, HCT116 and Caco2) using MTT assay in vitro were explored. Among them, thirteen compounds (17a, 17b, 18a, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, and 23b) exhibited significant inhibitory activity against the tested cancer cell lines. The structure-activity relationships (SARs) of bromophenol derivatives were discussed. The promising candidate compound 17a could induce cell cycle arrest at G0/G1 phase and induce apoptosis in A549 cells, as well as caused DNA fragmentations, morphological changes and ROS generation by the mechanism studies. Furthermore, compound 17a suppression of Bcl-2 levels (decrease in the expression of the anti-apoptotic proteins Bcl-2 and down-regulation in the expression levels of Bcl-2) in A549 cells were observed, along with activation caspase-3 and PARP, which indicated that compound 17a induced A549 cells apoptosis in vitro through the ROS-mediated apoptotic pathway. These results might be useful for bromophenol derivatives to be explored and developed as novel anticancer drugs.

[In vivo transdermal penetration enhancing activity of essential oil from Zanthoxyli Pericarpium by using microdialysis technique].

The aim of this paper is to investigate the topical pharmacodynamics behavior of different lipophilic model drugs after treatment with essential oil from Zanthoxyli Pericarpium by using the cutaneous microdialysis technique, and then evaluate its in vivo transdermal penetration enhancing properties. Two traditional Chinese medicine active components, namely tetramethylpyrazine and puerarin, were chosen as lipophilic and hydrophilic model drugs, respectively. Firstly, the concentration difference method was employed to measure the in vitro recovery rate and loss of the microdialysis probe, and the in vivo recoveries of two model drugs were determined by using the retrodialysis method. Secondly, the skin pharmacodynamics behaviors of two model drugs were studied after treatment with different concentrations of the essential oil, and the well-established and standard penetration enhancer Azone was selected as a positive control. It was found that the recovery of microdialysis probe was equal to its loss for two model drugs, with no interaction between drugs in dialysis membranes. The retrodialysis studies revealed that the in vivo recovery of tetramethylpyrazine and puerarin were 59.17%, 19.85%, respectively. The skin pharmacodynamics studies showed that the essential oil could facilitate the transdermal absorption of tetramethylpyrazine in a concentration-dependent manner, and the enhancement ratio (ER) for 5% essential oil was 98.64, which was higher than that of the optimum concentration of Azone (3% Azone, ER=89.11). Meanwhile, the Zanthoxyli Pericarpium could effectively promote the transdermal permeation of the puerarin in a concentration-dependent manner. Hence, this study further confirmed that the Zanthoxyli Pericarpium had excellent penetration-enhancing activity as a natural transdermal penetration enhancer, providing data support for its application in traditional Chinese medicine external preparations.

Design, synthesis and biological evaluation of uncharged catechol derivatives as selective inhibitors of PTP1B.

Protein tyrosine phosphatases 1B (PTP1B) is a promising and validated therapeutic target to effectively treat T2DM and obesity. However, the development of charged PTP1B inhibitors was restricted due to their low cell permeability and poor bioavailability. Based on active natural products, two series of uncharged catechol derivatives were identified as PTP1B inhibitors by targeting a secondary aryl phosphate-binding site as well as the catalytic site. The most potent inhibitor 22 showed an IC50 of 0.487 µM against PTP1B and strong selectivity (27-fold) over TCPTP. Kinetic studies were also performed that 22 act as a competitive PTP1B inhibitor. The treatment of C2C12 myotubes with 22 markedly increased the phosphorylation levels of IRß, Akt and IRS1 phosphorylation. The similarity of its action profiling with that produced by insulin suggested its potential as a new non-insulin-dependent drug candidate.

Application of Fluorine in Drug Design During 2010-2015 Years: A Mini-Review.

BACKGROUND: The widespread application of fluorine in drug design benefits from distinctive properties. Incorporation of fluorine can positively modulate certain pharmacokinetics properties, including lipophilicity, eletrophilicity, metabolic stability, chemical stability, et al., which were of interest to medicinal chemists. Herein, fluorinated compounds, which have been designed and evaluated for anticancer, antimicrobial, anti-inflammatory and antivirus activity, et al. during the last 6 years (2010-2015) are summarized. CONCLUSION: The emphasis is to highlight the importance of fluorinated compounds and the changes in the properties of compounds when introducing fluorine atom.

Small molecules as potent protein tyrosine phosphatase 1B (PTP1B) inhibitors documented in patents from 2009 to 2013.

Diabetes mellitus, including type 1 and type 2 diabetes mellitus (2-DM) are the main threats to human health in the worldwide. Protein tyrosine phosphatase 1B (PTP1B) is a promising molecular level legitimate therapeutic target in the effective management of 2-DM. For the search of potent PTP1B inhibitors, much investigation has revealed a large number of small-molecule compounds obtained from natural sources or prepared by synthesis/semi-synthesis with various skeletons and promising anti-PTP1B activities in the treatment of 2-DM. Although some reviews on the development of PTP1B inhibitors have been published, they were mainly concentrated on the results reported in journal articles. In this review, we will provide an overview of the developments of the potent PTP1B inhibitors claimed in recent patents during the past five years (2009-2013) with their structural features and biological features, as well as the structure-activity relationships (SARs) and strategies for finding potent and specific PTP1B inhibitors. This paper will provide valuable information for understanding the current anti-PTP1B investigation and developing potent PTP1B inhibitors as treating 2-DM drugs.

Design, synthesis and biological evaluation of novel bromophenol derivatives incorporating indolin-2-one moiety as potential anticancer agents.

A series of bromophenol derivatives containing indolin-2-one moiety were designed and evaluated that for their anticancer activities against A549, Bel7402, HepG2, HeLa and HCT116 cancer cell lines using MTT assay in vitro. Among them, seven compounds (4g-4i, 5h, 6d, 7a, 7b) showed potent activity against the tested five human cancer cell lines. Wound-healing assay demonstrated that compound 4g can be used as a potent compound for inactivating invasion and metastasis by inhibiting the migration of cancer cells. The structure-activity relationships (SARs) of bromophenol derivatives had been discussed, which were useful for exploring and developing bromophenol derivatives as novel anticancer drugs.

Sesquiterpenes from Laurencia similis.

One new sesquiterpene, (4E)-1-bromo-5-[(1'S*,3'R*)-3'-bromo-2',2'-dimethyl-6'-methylenecyclohexyl]-3-methylpent-4-ene-2,3-diol (1), and fifteen known sesquiterpenes, isopalisol (2), luzonensol (3), palisadin B (4), aplysistatin (5), palisadin A (6), 4-hydroxyl-palisudin C (7), 5-acetoxypalisadin B (8), 10-hydroxyaristolan-9-one (9), aristol-8-en-1-one (10), aristolan-9-en-1-one (11), aristolan-1(10)-en-9-one (12), aristolan-1(10)-en-9-ol (13), aristolan-1(10),8-diene (14), aristolan-1,9-diene (15) and aristofone (16), were isolated from a sample of marine red alga Laurencia similis. Their structures were established by detailed NMR spectroscopic analysis and comparison with literature data. Compounds 2-9, and 16 were isolated for the first time from this species. All these metabolites were submitted for a cytotoxicity assay against the tumor cell line BEL7402 (human liver adenocarcinoma), but all of them were found inactive (IC(50 )> 10 microg/mL).

[PTP1B inhibitory activities of bromophenol derivatives from algae].

OBJECTIVE: To study the protein tyrosine phosphatase-1B (PTP1B) inhibitory activity of natural products from algae aiming at searching for new way for the treatment of type 2 diabetes mellitus (T2DM) and obesity. METHOD: Bromophenols derivatives from algae were screened against the PTP1B by the colorimetric assay with GST/PTP1B fusion protein. The Me2SO was distributed as the full enzyme activity, and Na3VO4 (IC50 2 micromol L(-1)) was distributed as the positive control. Inhibition rate was assayed and IC50 were calculated by LOGIT method. RESULT: Three bromophenols from Rhodomela confervoides and Leathesia nana, 3, 4-dibromo-5-(methoxymethyl)-1, 2-benzenediol (1), 2-methyl-3-(2, 3-dibromo4, 5-dihydroxy)-propylaldehyde (2) and 3-(2, 3-dibromo-4, 5-dihydroxy-phenyl)-4-bromo-5, 6-dihydroxy-1, 3-dihydroiso-benzofuran (3) showed significant inhibitory activity against PTP1B. IC50 values were 3.4 +/- micromol L(-1), 4.5 micromol L(-1) and 2.8 micromol L(-1), respectively. CONCLUSION: The results prove that three bromophenol derivatives from algae with significant inhibitory activity against PTP1B were potential and effective therapeutic agents for treatment of T2DM and obesity.

Chemical constituents of the red alga Laurencia tristicha.

Six new sesquiterpenes, 10-hydroxy-epiaplysin (1), 10-hydroxy-aplysin (2), 10-hydroxy-debromoepiaplysin (3), aplysin-9-ene (4), epiaplysinol (5) and debromoepiaplysinol (6), together with 13 known compounds (7-19), have been isolated from the red alga Laurencia tristicha. The structures of 1-6 were determined by spectroscopic methods including IR, EI-MS, HREI-MS, and 1D and 2D NMR techniques. All compounds were obtained from this species for the first time and were tested for cytotoxic activities against several human cancer cell lines including lung adenocarcinoma (A549), stomach cancer (BGC-823), hepatoma (Bel 7402), colon cancer (HCT-8) and HeLa cell lines. Compound 6 showed selective cytotoxicity against HeLa cell line with IC(50) 15.5 microM, cholest-5-en-3beta,7alpha-diol (14) was toxic to all tested cell lines with IC(50) values of 16.8, 5.1, 0.5, 0.5, and 0.3 microM, respectively, and other compounds were inactive (IC(50)>10 microg/ml).

[Studies on chemical constitutes of Acantophora spicifera].

OBJECTIVE: To study the chemical constitutes of Acantophora spicifera. METHOD: Compounds were isolated by normal phase silica gel and Sephadex LH-20 gel column chromatography, and reverse-phase HPLC, as well as recrystallization. Their structures were elucidated by spectroscopic methods. RESULT: Seven compounds were isolated from A. spicifera and their structures were identified as aplysin (1), loloilide (2), (R)-(-)-dehydrovomifoliol (3), uracil (4), thymine (5), 1-methoxy-4-(1-propenyl) benzene (6). CONCLUSION: The compounds were obtained from this genus for the first time. Compound 6 was firstly obtained from marine organisms.

Effect of ethanol extract of alga Laurencia supplementation on DNA oxidation and alkylation damage in mice.

Laurencia terpenoid extract (LET) had been extracted from the red alga Laurencia tristicha. The study is to investigate the effects of LET supplementation on DNA oxidation and alkylation damages in mice. Forty healthy Kunming mice weighing between 18g and 25g were randomly assigned into 4 groups, each consisting of ten animals. The mice were orally intubated respectively for 60 days with the designed concentrations of LET (25, 50,100mg/ kg b.w.) for three exposed groups and salad oil (0.2 ml) for the blank group. Food and water were free for the animals. Mice in the blank and exposed groups were sacrificed after the last treatment and the blood of each animal was quickly taken for further experiments. The spontaneous and oxidized DNA damages of peripheral lymphocytes induced by H2O2 were analysed by SCGE. O6-Methy-guanine (O6-MeG) was measured by high performance capillary zone electrophoresis. There was no significantly difference in DNA spontaneous damage on peripheral lymphocytes of all the mice. The oxidative DNA damage in the 50 mg/Kg body weight supplement group are 286AU with the oxidation of 10 micromol/L H2O2, significantly lower than the blank group 332AU (p<0.05). The contents of O6-MeG in plasma in the 50 mg/kg b.w. and 100mg/kg b.w. supplement group were 1.50 micromol/L and 1.88 micromol/L, significantly lower than that of the blank group, which was 2.89 micromol/L(p<0.05). The results from the present study indicated that the LET were rich in terpenoids and safety to be taken orally and it could improve antioxidative and decrease DNA damage effectively.