[Show abstract][Hide abstract] ABSTRACT: An efficient synthetic route was developed for the large-scale preparation of (±)-Yanglingmycin and its analogues. Three series of derivatives of (±)-Yanglingmycin were synthesized and the structures of all compounds were elucidated by analyses of NMR and ESI-MS spectra data. Moreover, their antibacterial activities against seven species of bacteria were systematically evaluated by the micro-broth dilution method, most of which displayed considerable activity. It was worth noting that compounds 5b, 5c, 5d, 6g, and 7 were found to be the most promising leading candidates, with peak MIC values of 0.98 μg·mL(-1) for Bacillus subtilis, which is superior to positive controls (MIC = 3.91 μg·mL(-1)). The above results might lay the firm foundation for the design and synthesis of novel antibacterial drugs based on (±)-Yanglingmycin.
[Show abstract][Hide abstract] ABSTRACT: Bacillus thuringiensis (Bt) Cry toxins from the Cry1A family demonstrate significantly different toxicities against members of the family Noctuidae for unknown reasons. In this study, membrane potential was measured and analyzed in freshly isolated midgut samples from Mythimna separata and Agrotis ipsilon larvae under oral administration and in vitro incubation with Bt toxin Cry1Ab to elucidate the mechanism of action for further control of these pests. Bioassay results showed that the larvae of M. separata achieved a LD50 of 258.84 ng/larva at 24 h after ingestion; M. separata larvae were at least eightfold more sensitive than A. ipsilon larvae to Cry1Ab. Force-feeding showed that the observed midgut apical-membrane potential (Vam) of M. separata larvae was significantly depolarized from —82.9 ± 6.6 mV to —19.9 ± 7.2 mV at 8 h after ingestion of 1 μg activated Cry1Ab, whereas no obvious changes were detected in A. ipsilon larvae with dosage of 5 μg Cry1Ab. The activated Cry1Ab caused a distinct concentration-dependent depolarization of the apical membrane; Vam was reduced by 50% after 14.7 ± 0.2, 9.8 ± 0.4, and 7.6 ± 0.6 min of treatment with 1, 5, and 10 µg/mL Cry1Ab, respectively. Cry1Ab showed a minimal effect on A. ipsilon larvae even at 20 µg/mL, and Vam decreased by 26.3% ± 2.3% after 15 min. The concentrations of Cry1Ab displayed no significant effect on the basolateral side of the epithelium. The Vam of A. ipsilon (—33.19 ± 6.29 mV, n = 51) was only half that of M. separata (—80.94 ± 6.95 mV, n = 75). The different degrees of sensitivity to Cry1Ab were speculatively associated with various habits, as well as the diverse physiological or biochemical characteristics of the midgut cell membranes.
[Show abstract][Hide abstract] ABSTRACT: Sixty 2-aryl-4,5-dihydrothiazoles were designed and synthesized in yields ranging from 64% to 89% from cysteine and substituted-benzonitriles via a novel metal- and catalyst-free method. The structures of the title compounds were confirmed mainly by NMR spectral data analysis. Antibacterial activity assays showed that the compounds (S)-2-(2'-hydroxyphenyl)-4-hydroxy-methyl- 4,5-dihydrothiazole (7h) and (R)-2-(2'-hydroxyphenyl)-4-hydroxymethyl-4,5-dihydro-thiazole (7h') exhibited significant inhibition against Ralstonia solanacearum, Pseudomonas syringae pv. actinidiae, Bacillus subtilis and Bacillus cereus, with minimum inhibitory concentrations (MICs) ranging from 3.91 to 31.24 μg·mL(-1). The effect of substituents showed that not only electron-withdrawing groups, but also electron-donating groups could abolish the antibacterial activities unless a 2'-hydroxy group was introduced on the 2-aryl substituent of the 4,5-dihydrothiazole analogues. The results of scanning electron microscope (SEM) and fatty acid exposure experiments indicated that these antibacterial compounds influence fatty acid synthesis in the tested bacteria.
[Show abstract][Hide abstract] ABSTRACT: Celangulin V, an insecticidal compound isolated from the root bark of Chinese bittersweet, can affect the digestive system of insects. However, the mechanism of how Celangulin V induces a series of symptoms is still unknown. In this study, affinity chromatography was conducted through coupling of Celangulin V-6-aminoacetic acid ester to the CNBr-activated Sepharose 4B. SDS-PAGE was used to analyze the collected fraction eluted by Celangulin V. Eight binding proteins (Zinc finger protein, Thioredoxin peroxidase (TPx), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), SUMO E3 ligase RanBP2, Transmembrane protein 1, Actin, APN and V-ATPase) were obtained and identified by LC/Q-TOF-MS from the midgut of Mythimna separata larvae. The potential of these proteins to serve as target proteins involved in the insecticidal activity of Celangulin V is discussed.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND1β, 2β, 4α, 6α, 8β, 9α, 12-hepthydroxyl-β-dihydroagarofuran is the main skeleton of β-dihydroagarofuran sesquiterpenoids which exhibit excellent insecticidal activity. To further study the structure-activity relationship of β-dihydroagarofuran sesquiterpenoids towards finding novel botanical pesticides, two series of new structurally modified ether analogues were designed and synthesized, and their insecticidal activities were evaluated.RESULTSTwenty two ether derivatives were synthesized using 1β, 2β, 4α, 6α, 8β, 9α, 12-hepthydroxyl-β-dihydroagarofuran as starting material. And The bioassay results indicated that most of the derivatives, particularly compounds 5.1.2, 5.1.3, 5.1.7, 5.2.3, 5.2.6 and 5.2.7, exhibited significant insecticidal activity against the 3rd instar larvae of M. srparata. Most importantly, compound 5.2.7 showed the lowest LD50 value of 29.2 ug/g among these synthesized compounds, which provides some important hints for further design, synthesis and structural modification of β-dihydroagarofuran sesquiterpenoids towards developing novel botanical insecticides.CONCLUSION
The structure-activity relationship illustrated that the moiety at the 1-position affected the insecticidal activity significantly, and that specifically, the derivatives with two or three carbon atoms at the 1-position showed promising insecticidal activity with mortality over 60%, while those with o-F-Bn and p-F-Bn at the 6-position showed similar activity.
No preview · Article · May 2015 · Pest Management Science
[Show abstract][Hide abstract] ABSTRACT: Periplocoside NW (PSNW) with pregnane glycoside skeleton is a novel insecticidal compound isolated from the root bark of Periploca sepium Bunge. This compound has a potent stomach poisoning activity against several insect pests. In this study, we observed the intoxication symptoms, investigated the histopathological effects and carried out immuno-electron microscopic localization of PSNW on the midgut epithelium of oriental armyworm Mythimna separata Walker larvae for better understanding its action mechanism against insects. Ultrastructural observations showed that cell damages caused by PSNW in the midgut of M. separata larvae are related to the degeneration of brush border microvilli. The dissolution of cytoskeletal structures in the interior and on the surface of microvilli was responsible for the decrease in size and eventual disappearance of microvilli when bubbles of cytoplasmic substances protrude into the midgut lumen of M. separata, thus resulting in cell death. The immuno-electron microscopic localization research showed that gold particle appeared on the microvilli layer of the midgut of M. separate larvae firstly. The density of gold particle gradually added with the time, and finally microvilli layer was destructed severely. Meantime, the gold particles were also presented to the intracellular organelle membrane and the organelles also were destructed. Therefore, we proposed that this membrane system on insect midgut epithelium cells is the initial acting site of PSNW against insects.
No preview · Article · Oct 2014 · Pesticide Biochemistry and Physiology
[Show abstract][Hide abstract] ABSTRACT: This Letter describes the on-going SAR efforts based on ML297, a potent, efficacious and selective GIRK1/2 activator (∼10-fold vs GIRK1/4 and inactive on GIRK2/3) via an iterative parallel synthesis approach. The chemical optimization at the 3-position of pyrazole within ML297 indicated that various functionalized 3-cyclopropyl moieties modulated GIRK pharmacology between inhibitor/activator within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas. Importantly, novel 'molecular switches' that modulated the mode of pharmacology from inhibitor to activator was discovered on both the 3-cyclopropyl and N-phenyl moiety of the pyrazole core, providing the first highly selective GIRK1/2 activator.
[Show abstract][Hide abstract] ABSTRACT: Isolated from Dictamnus dasycarpus Turcz., fraxinellone exhibited multiple bioactivities against insects. In the present paper, the changes of digestive enzymes and detoxification enzymes of Mythimna separata Walker (5th instar larvae), treated with fraxinellone, were investigated. Compared with those of the control, the α-amylase activity of the fraxinellone-treated 5th instar larvae was inhibited, whereas the level of their protease activity was increased. Based upon further studies on the specific proteases, the levels of the active alkaline trypsin-like enzyme (BApNA as the substrate) and the chymotrypsin-like enzyme (BTEE as the substrate) activities of the treated larvae were declined; however, the level of activity of the weak alkaline trypsin-like enzyme (TAME as the substrate) of the treated ones was increased. Meanwhile, the activities of two detoxification enzymes, such as carboxylesterase (CarE) and glutathione S-transferase (GST), of the treated larvae were increased to some extent, but the activities of NADPH-P450 reductase and O-demethylase of the treated ones declined. Therefore, protease (especially the weak alkaline trypsin-like enzyme), CarE and GST played important roles in the metabolism of fraxinellone in the midgut of Mythimna separata (M. separata).
[Show abstract][Hide abstract] ABSTRACT: The vacuolar (H+)-ATPase (V-ATPase) of insect, which is composed of membrane-bound V0 complex and peripheral V1 complex, participates in lots of important physiological process. Subunit H, as a subunit of V1 complex, plays a vital role in bridging the communication between V1 and V0 complexes and interaction with other proteins. Yeast subunit H has been successfully crystallized through expression in E. coli, but little is known about the structure of insect subunit H. In this study, we cloned, expressed and purified the subunit H from midgut of Mythimna separata Walker. Through RACE (rapidly amplification of cDNA ends) technique, we got 1807 bp full length of subunit H, and to keep the nature structure of subunit H, we constructed Baculovirus expression vector with His-tag in the C-terminal and expressed the recombinant protein in insect sf9 cells, thereafter, purified the recombinant protein by Ni-NTA columns. Results of SDS-PAGE, western blotting and mass spectrometry showed that the recombinant protein was successfully expressed. The method of expressing and purifying M. separata subunit H will provide a foundation for obtaining the crystal of subunit H and further study of the design of novel insecticides based on its structure and function.
Full-text · Article · Sep 2014 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Herein we report the discovery and SAR of an indole-based protease activated receptor-4 (PAR-4) antagonist scaffold derived from a similarity search of the Vanderbilt HTS collection, leading to MLPCN probe ML354 (VU0099704). Using a novel PAC-1 fluorescent αIIbβ3 activation assay this probe molecule antagonist was found to have an IC50 of 140nM for PAR-4 with 71-fold selectivity versus PAR-1 (PAR-1IC50=10μM).
No preview · Article · Aug 2014 · Bioorganic & Medicinal Chemistry Letters
[Show abstract][Hide abstract] ABSTRACT: In order to develop new biorational pesticides and clarify the potential structural factors needed for the biological activity of celangulin-V analogues, thirty novel nitrogenous derivatives were designed and synthesized. The single crystal structure of celangulin-V is reported for the first time and provides a more accurate structure than that previously reported. The structures of all the new derivatives were confirmed by either NMR or ESI-MSn analysis. Insecticidal activities of these compounds were tested against the third-instar larvae of Mythimna separata. One derivative (1-6) showed higher insecticidal activity than celangulin-V, with a KD50 of 231.2 microg.g(-1), while two compounds (2-13 and 2-14) exhibited lower insecticidal activities; the others revealed no activity at a concentration of 20 mg mL(-1). The results support the view that celangulin-V has the potential to be a lead structure of semi-synthetic green insecticides.
No preview · Article · Jun 2014 · Natural product communications
[Show abstract][Hide abstract] ABSTRACT: Periplocoside NW (PSNW) is a novel insecticidal compound isolated from the root bark of Periploca sepium Bunge and has potent stomach toxicity against some insect pests. Previous studies showed that the Mythimna separata larva is sensitive to PSNW, but the Agrotis ispilon larva is insensitive. In this study, preliminary target localization on the midgut of M. separata larvae was conducted via a fluorescence labeling technique. A comparative ultrastructural study on the effects of PSNW on the midguts of M. separata and A. ispilon larvae was performed. Symptom observation results showed that typical stomach toxicity was induced by PSNW in M. separata larvae. Fluorescence localization results showed that PSNW binds to the midgut cells of M. separata larvae. Ultrastructure observations showed destruction of the microvilli, organelle, and cytomembrane in the midgut cells of M. separata larvae, whereas no obvious changes were observed in midgut cells of A. ispilon larvae. These results were consistent with the insecticidal activity of PSNW. Therefore, PSNW might act on the midgut tissues of the insects, and one or more binding sites of PSNW may exist in M. separata larvae midgut cell cytomembranes.
[Show abstract][Hide abstract] ABSTRACT: Go catalytic! A highly enantioselective hydrogenation of β,β-disubstituted nitroalkenes and isomeric mixtures of nitroalkenes by using a Rh/DuanPhos catalytic system under basic conditions has furnished a convenient approach to β-chiral nitroalkanes, which are otherwise not so easy to make.
No preview · Article · Jan 2014 · Chemistry - A European Journal
[Show abstract][Hide abstract] ABSTRACT: In our continuous investigation of metabolites of Streptomyces alboflavus 313, NW-G12 (1), a novel nonchlorinated analogue of NW-G01, was obtained as a trace constituent in the weak polarity part and a known desertomycin A (2) was also isolated from the fermentation broth in the strong polarity part. The structures of compounds 1 and 2 were established by comprehensive analysis of 1D and 2D NMR spectral data. Moreover, compounds 1 and 2 showed strong antibacterial activities against Bacillus cereus, Staphylococcus aureus, and Bacillus subtilis, with MICs of less than 10 μg/mL, but both show no antibacterial activities against two gram-negative bacteria.
No preview · Article · Nov 2013 · Chemistry of Natural Compounds
[Show abstract][Hide abstract] ABSTRACT: This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (∼10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.
No preview · Article · Jun 2013 · Bioorganic & medicinal chemistry letters
[Show abstract][Hide abstract] ABSTRACT: The highly linear-selective hydroaminomethylation of styrenes is very challenging. Herein, an efficient, highly chemoselective, and linear-selective hydroaminomethylation (l/b up to >99:1) of styrenes using Rh(nbd)2SbF6 with a pyrrole-based 3,3',5,5'-substituted tetraphosphorus ligand is documented. This is in sharp contrast to other available processes leading to branched amines and provides a novel atom economic approach to 3-arylpropylamines.
[Show abstract][Hide abstract] ABSTRACT: In order to develop novel biorational pesticides, twelve new ether derivatives of 1β,4α,6α,9α-tetrahydroxy-2β,12-epoxymethano-β-dihydroagarofuran (3) were synthesized. The structure of the important intermediate 3was confirmed by X-ray crystallography, and the new derivatives (3.1-3.12) were elucidated by IR, 1H NMR, 13C NMR and 2D NMR spectroscopic and ESI-MS analysis. Insecticidal activities of these derivatives were tested against the third-instar larvae of Mythimna separata. Though most of the derivatives (3.1-3.4, 3.6, 3.8, 3.9-3.12) revealed no obvious activities at the concentration of 10 mg/mL, two compounds 3.5and 3.7, with KD50values of 12.9 μg/g and 7.8 μg/g, respectively, showed much higher insecticidal activities than celangulin-V, with a KD50of 321.4 μg/g, the main insecticidal component from the root bark of Chinese bittersweet, Celastrus angulatus Max. The results showed that β-dihydroagarofuran has the potential to be a lead structure for semi-synthetic green insecticides.
[Show abstract][Hide abstract] ABSTRACT: The new compound Z-4-2 was isolated from the fermentation broth of Streptomyces djakartensis NW35, together with the known compound N-acetyltryptamine (Z-9-2) by bioassay-guided fractionation. Its chemical structure was elucidated as (E)-2-methoxy-1,4 naphthoquinone-1-oxime (Z-4-2) mainly by NMR analyses and MS spectral data. Their antibacterial activities against bacteria were evaluated by the filter paper method. The results of indicated that these compounds possess significant antibacterial activities.