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A novel series of fatty acid synthase (FAS) inhibitors with D-(-)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC 50 values in the range of 13.68 ± 1.52-33.19 ± 1.39 μM, reference inhibitor C75 has IC 50 value of 13.86 ± 2.79 μM. Eight compounds (3c, 3d, 3e, 3f, 3j, 3m, 3q and 3r) also displayed inhibitory effect on lipid accumulation in human HepG2 cells. Additionally, the molecular docking study revealed that compound 3m having good inhibition activity against FAS and lipid accumulation also showed promising binding affinities with hFAS, while its binding model with hFAS (PDB ID: 4PIV) was different from that of reference compound C75., (Copyright © 2019. Published by Elsevier Ltd.)

The herb couple has special clinical significance in reducing the toxicity and increasing the efficacy of drugs. The combination of Radix Angelicae Dahuricae (Baizhi, BZ) and Rhizoma Chuanxiong (ChuanXiong, CX) is a traditional herb couple. The combination performs better than the CX extract alone in the treatment of migraine and has been used for thousands of years. However, the specific compatibility mechanisms are still unclear. Ligustilide, dl-3-n-butylphthalide and senkyunolide A are the major active ingredients in CX and BZ-CX decoction. However, a comprehensive study of the pharmacokinetics of CX has not been carried out. A gas chromatography-mass spectroscopy (GC-MS) method with high selectivity, sensitivity and accuracy was developed. An SH-Rxi-5Sil (30 m × 0.25 mm i.d., and 0.25 μm film thickness) column was employed in the GC separation. Selectivity, linearity, precision, accuracy, recovery, matrix effect and stability were used to validate the current GC-MS method. Using the validated method, this is the first time to study on the comparative pharmacokinetics of ligustilide, dl-3-n-butylphthalide and senkyunolide A from CX alone and BZ-CX decoction in rat plasma. The pharmacokinetic parameters (C max , T max , T 1/2 , AUC 0-t , AUC 0-∞ and CLz/F) of all of the detected ingredients showed significant differences between the two groups (P < 0.05). The results are helpful for further investigation of the compatibility mechanism of BZ-CX decoction., (© 2019 John Wiley & Sons, Ltd.)

Numerous reports assigning ( Z )-ligustilide ( 1 ) the role of a major bioactive principle in Apiaceae botanicals are called into question by the recurrent demonstrations of 1 being an unstable, rapidly degrading compound, ultimately leading to dynamic residual complexity. While Angelica sinensis is recognized for its therapeutic value in (peri-)menopausal symptom management, its purported active principle, 1 , represents a typical example of the instability-bioactivity chasm of botanicals. To help bridge the gap, this study used both the essential oil and purified 1 obtained from A. sinensis to investigate the factors that influence the chemical transformation of 1 , the products formed, and the rationale for monitoring 1 in natural product preparations. Countercurrent separation was used to purify 1 from a supercritical fluid extract of A. sinensis , achieving 93.4% purity in a single step. Subsequent purification by preparative HPLC afforded 1 with a 98.0% purity. Providing a mass balance setting, we monitored chemical changes occurring to highly purified 1 under various conditions and at different time points, in sealed NMR tubes by quantitative 1 H NMR (qHNMR). The nondestructive nature of NMR enabled a comprehensive assessment of degradation products. Moreover, in being a mole-based determination, the total intensity (integral) of all NMR signals intrinsically represents the theoretical mass balance within the sample solution. The results demonstrated that 1 is most stable while within the original plant material. Exposure to light had a profound impact on the chemical transformation of 1 , leading to the formation of ligustilide dimers and trimers, as verified by both NMR and LC-HRMS studies. Moreover, the results shown for 1 , augmented by other recent outcomes, have serious implications for the meaningful biological evaluation of NPs that exhibit instability/reactivity, while having a plethora of "promising" bioactivities reported in the literature and being frequently associated with unsubstantiated health claims.

The actin-related protein complex 2/3 (Arp2/3) generates branched actin networks important for many cellular processes such as motility, vesicular trafficking, cytokinesis, and intercellular junction formation and stabilization. Activation of Arp2/3 requires interaction with actin nucleation-promoting factors (NPFs). Regulation of Arp2/3 activity is achieved by endogenous inhibitory proteins through direct binding to Arp2/3 and competition with NPFs or by binding to Arp2/3-induced actin filaments and disassembly of branched actin networks. Arp2/3 inhibition has recently garnered more attention as it has been associated with attenuation of cancer progression, neurotoxic effects during drug abuse, and pathogen invasion of host cells. In this review, we summarize current knowledge on expression, inhibitory mechanisms and function of endogenous proteins able to inhibit Arp2/3 such as coronins, GMFs, PICK1, gadkin, and arpin. Moreover, we discuss cellular consequences of pharmacological Arp2/3 inhibition.

Atherosclerosis is initiated by the local inflammation response to lipid deposition, and the most commonly administered antiatherogenic drugs are statins. Based on traditional Chinese medicine (TCM) evidence, we aimed to find effective therapeutic agents other than statins. A TCM, Suxiao Jiuxin Pill (SX), has been widely used in curing cardiovascular diseases for thirty years. In this paper, a combination of pharmacologic studies and RNA-Seq transcriptomics were employed to explore the pharmacodynamic advantages of SX over atorvastatin in the ApoE -/- mouse. 113 differentially expressed genes that were modulated by SX to a greater degree than atorvastatin were primarily involved in immunomodulation. The expression of BTK, AKT1, c-jun and CD137 was effectively regulated by SX with better effect than atorvastatin. Then a dual-luciferase reporter assay for NF-κB inhibition was applied to identify active components in SX. As a result, Senkyunolide A (Sen A) and Ligustilide (Lig), the key immunomodulatory ingredients in SX, were found to inhibit the expression of CD137 which is a diagnostic biomarker in atherosclerosis. It was further confirmed that Lig effectively suppressed the expression of AP-1 and NF-κB and the phosphorylation of AKT. Therefore, Lig achieved its CD137 inhibition through suppressing the expression of AP-1 and AKT/NF-κB signaling pathway, which partly explains the immunomodulation of SX in atherosclerosis. Above all, phthalides may be the primary components of SX improving immune and inflammation response in atherosclerosis., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A library of isopulegol-based bi-, tri- and tetrafunctional chiral ligands has been developed from commercially available (-)-isopulegol and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. Michael addition of primary amines towards α -methylene- γ -butyrolactone, followed by reduction, was accomplished to provide aminodiols in highly stereoselective transformations. Stereoselective epoxidation of (+)-neoisopulegol, derived from natural (-)-isopulegol, and subsequent oxirane ring opening with primary amines afforded aminodiols. The regioselective ring closure of N -substituted aminodiols with formaldehyde was also investigated. Hydroxylation of (+)-neoisopulegol resulted in diol, which was then transformed into aminotriols by aminolysis of its epoxides. Dihydroxylation of (+)-neoisopulegol or derivatives with OsO 4 /NMO gave neoisopulegol-based di-, tri- and tetraols in highly stereoselective reactions. The antimicrobial activity of aminodiol and aminotriol derivatives as well as di-, tri- and tetraols was also explored. In addition, structure-activity relationships were examined by assessing substituent effects on the aminodiol and aminotriol systems., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results. Sources of funding for the study.

Synthetically derived ( Z )-ligustilide ( 1 ) has been subjected to photochemically-promoted dimerization processes under a range of conditions. By such means, varying distributions of the dimeric natural products tokinolides A-C ( 4 , 3 , and 6 , respectively) and riligustilide ( 5 ) as well certain related (isomeric) compounds have been obtained. The structures of three of them have been confirmed by single-crystal X-ray analysis. The biosynthetic implications of the outcomes of this study are discussed.

Many Gram-negative bacteria can regulate gene expression in a cell density-dependent manner via quorum-sensing systems using N -acyl-homoserine lactones (AHLs), which are typical quorum-sensing signaling molecules, and thus modulate physiological characteristics. N -acyl-homoserine lactones are small chemical molecules produced at low concentrations by bacteria and are, therefore, difficult to detect. Here, a biosensor system method and liquid chromatography-tandem mass spectrometry were combined to detect and assay AHL production. As demonstrated by liquid chromatography-tandem mass spectrometry, Gluconacetobacter xylinus CGMCC No. 2955, a Gram-negative acetic acid-producing bacterium and a typical bacterial cellulose (BC) biosynthesis strain, produces six different AHLs, including N -acetyl-homoserine lactone, N -butanoyl-homoserine lactone, N -hexanoyl-homoserine lactone, N -3-oxo-decanoyl-homoserine lactone, N -dodecanoyl-homoserine lactone, and N -tetradecanoyl-homoserine lactone. Gluconacetobacter sp. strain SX-1, another Gram-negative acetic acid-producing bacterium, which can synthesize BC, produces seven different AHLs including N -acetyl-homoserine lactone, N -butanoyl-homoserine lactone, N -hexanoyl-homoserine lactone, N -3-oxo-octanoyl-homoserine lactone, N -decanoyl-homoserine lactone, N -dodecanoyl-homoserine lactone, and N -tetradecanoyl-homoserine lactone. These results lay the foundation for investigating the relationship between BC biosynthesis and quorum-sensing systems.

Three new γ -hydroxyl butenolides ( 1 - 3 ), a pair of new enantiomeric spiro-butenolides ( 4a and 4b ), a pair of enantiomeric cyclopentenones ( 5a new and 5b new natural), and six known compounds ( 6 - 11 ), were isolated from Aspergillus sclerotiorum . Their structures were established by spectroscopic data and electronic circular dichroism (ECD) spectra. Two pairs of enantiomers [(+)/(-)- 6c and (+)/(-)- 6d ] obtained from the reaction of 6 with acetyl chloride (AcCl) confirmed that 6 was a mixture of two pairs of enantiomers. In addition, the X-ray data confirmed that 7 was also a racemate. The new metabolites ( 1 - 5) were evaluated for their inhibitory activity against cancer and non-cancer cell lines. As a result, compound 1 exhibited moderate cytotoxicity to HL60 and A549 with IC 50 values of 6.5 and 8.9 µM, respectively, and weak potency to HL-7702 with IC 50 values of 17.6 µM. Furthermore, compounds 1 - 9 were screened for their antimicrobial activity using the micro-broth dilution method. MIC values of 200 μg/mL were obtained for compounds 2 and 3 towards Staphylococcus aureus and Escherichia coli , while compound 8 exhibited a MIC of 50 μ/mL towards Candida albicans .

The present study aimed to investigate the antibacterial activity of striatisporolide A (SA) against Escherichia coli (E. coli) and the underlying mechanism. Antibacterial activity was evaluated according to the inhibitory rate and zone of inhibition. The antibacterial mechanism was investigated by analyzing alkaline phosphatase (AKP) activity and ATP leakage, protein expression, cell morphology and intracellular alterations in E. coli. The results demonstrated that SA exerted bacteriostatic effects on E. coli in vitro. AKP activity and ATP leakage analysis revealed that SA damaged the cell wall and cell membrane of E. coli. SDS‑PAGE analysis indicated that SA notably altered the level of 10 and 35 kDa proteins. Scanning electron microscopy and transmission electron microscopy analyses revealed marked alterations in the morphology and ultrastructure of E. coli following treatment with SA. The mechanism underlying the antimicrobial effects of SA against E. coli may be attributed to its actions of disrupting the cell membrane and cell wall and regulation of protein level. The findings of the present study provide novel insight into the antimicrobial activity of SA as a potential natural antibacterial agent.

Smoke derived karrikinolide and trimethylbutenolide exerted neuroprotective effects against monoamine oxidase and acetylcholinesterase. Synthesis of potent analogs was achieved. Sulphur substitution in the bicyclic ring structure of KAR 1 displayed the most encouraging activity returning IC 50 values of 13.75 ± 0.001 μM and 0.03 ± 0.02 μM for monoamine oxidase A and B and 0.08 ± 0.006 μM for acetylcholinesterase. Neuroprotective butenolides may be particularly useful in the treatment of depressive disorders, Alzheimer's and Parkinson's diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

An electrospinning process was optimized to produce fibers of micrometric size with different combinations of polymeric and surfactant materials to promote the dissolution rate of an insoluble drug: firocoxib. Scanning Electron Microscopy (SEM) showed that only some combinations of the proposed carrier systems allowed the production of suitable fibers and further fine optimization of the technique is also needed to load the drug. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) suggest that the drug is in an amorphous state in the final product. Drug amorphization, the fine dispersion of the active in the carriers, and the large surface area exposed to water interaction obtained through the electrospinning process can explain the remarkable improvement in the dissolution performance of firocoxib from the final product developed.

Senescence Marker Protein (SMP30) is a metalloenzyme that shows lactonase activity in the ascorbic acid (AA) biosynthesis pathway in non-primate mammals such as a mouse. However, AA biosynthesis does not occur in the primates including humans. Several studies have shown the role of SMP30 in maintaining calcium homeostasis in mammals. In addition, it is also reported to have promiscuous enzyme activity with an organophosphate (OP) substrate. Hence, this study aims to recombinantly express and purify the SMP30 proteins from both mouse and human, and to study their structural alterations and functional deviations in the presence of different divalent metals. For this, mouse SMP30 (MoSMP30) as well as human SMP30 (HuSMP30) were cloned in the bacterial expression vector. Proteins were overexpressed and purified from soluble fractions as well as from inclusion bodies as these proteins were expressed largely in insoluble fractions. The purified proteins were used to study the folding conformations in the presence of different divalent cations (Ca2+, Co2+, Mg2+, and Zn2+) with the help of circular dichroism (CD) spectroscopy. It was observed that both MoSMP30 and HuSMP30 acquired native folding conformations. To study the metal-binding affinity, dissociation constant (Kd values) were calculated from UV-VIS titration curve, which showed the highest affinity of MoSMP30 with Zn2+. However, HuSMP30 showed the highest affinity with Ca2+, suggesting the importance of HuSMP30 in maintaining calcium homeostasis. Enzyme kinetics were performed with γ-Thiobutyrolactone and Demeton-S in the presence of different divalent cations. Interestingly, both the proteins showed lactonase activity in the presence of Ca2+. In addition, MoSMP30 and HuSMP30 also showed lactonase activity in the presence of Co2+ and Zn2+ respectively. Moreover, both the proteins showed OP hydrolase activities in the presence of Ca2+ as well as Zn2+, suggesting the metal-dependent promiscuous nature of SMP30., Competing Interests: The authors have declared that no competing interests exist.

Mankind is on the verge of a postantibiotic era. New concepts are needed in our battle to attenuate infectious diseases around the world and broad spectrum plant-inspired synergistic pharmaceutical preparations should find their place in the global fight against pathogenic microorganisms. To progress towards the discovery of potent antifungal agents against human pathologies, we embarked upon developing chemometric approach coupled with statistical design to unravel the origin of the anticandidal potential of a set of 66 essential oils (EOs). EOs were analyzed by GC-MS and tested against Candida albicans and C. parapsilosis (Minimal Inhibitory Concentration, MIC). An Orthogonal Partial Least Square (OPLS) analysis allowed us to identify six molecules presumably responsible for the anticandidal activity of the oils: (Z)-ligustilide, eugenol, eugenyl acetate, citral, thymol, and β-citronellol. These compounds were combined following a full factorial experimental design approach in order to optimize the anticandidal activity and selectivity index (SI = IC 50 (MRC 5 cells)/MIC) through reconstituted mixtures. (Z)-Ligustilide and citral were the most active compounds, while (Z)-ligustilide and eugenol were the two main factors that most contributed to the increase of the SI. These two terpenes can, therefore, be used to construct bioinspired synergistic anticandidal mixtures.

Three new butenolide derivatives, namely aspernolides N-P ( 1 - 3 ), together with six known analogues ( 4 - 9 ), were isolated from the ethyl acetate (EtOAc) extract of the deep sea-derived fungus Aspergillus terreus YPGA10. The structures of compounds 1 - 3 were determined on the basis of comprehensive analyses of the nuclear magnetic resonance (NMR) and mass spectroscopy (MS) data, and the absolute configurations of 1 and 2 were determined by comparisons of experimental electronic circular dichroism (ECD) with calculated ECD spectra. Compound 1 represents the rare example of Aspergillus -derived butenolide derivatives featured by a monosubstituted benzene ring. Compounds 6 - 9 exhibited remarkable inhibitory effects against α -glucosidase with IC 50 values of 3.87, 1.37, 6.98, and 8.06 μM, respectively, being much more active than the positive control acarbose (190.2 μM).

The natural alkaloid epiisopiloturine has recently become the focus of study for various medicinal properties, particularly for its anti-inflammatory and antischistosomal effect. The incorporation of active molecules in natural polymeric matrices has garnered increasing interest during recent decades. A new derivative of cashew gum successfully obtained by gum acetylation has shown great potential as a carrier in controlled drug release systems. In this work, epiisopiloturine was encapsulated in acetylated cashew gum nanoparticles in order to increase solubility and allow slow release, whereas the morphology results were supported by computer simulations. The particles were produced under a variety of conditions, and thoroughly characterized using light scattering and microscopic techniques. The particles were spherical and highly stable in solution, and showed drug incorporation at high levels, up to 55% efficiency. Using a dialysis-based in vitro assay, these particles were shown to release the drug via a Fickian diffusion mechanism, leading to gradual drug release over approximately 6 h. These nanoparticles show potential for the use as drug delivery system, while studies on their potential anti-inflammatory action, as well as toxicity and efficacy assays would need to be performed in the future to confirm their suitability as drug delivery candidates., (Copyright © 2019. Published by Elsevier B.V.)

Ligustilide (LIG) is the main lipophilic component of the Umbelliferae family of pharmaceutical plants, including Radix angelicae sinensis and Ligusticum chuanxiong. LIG shows various pharmacological properties associated with anti-inflammation and anti-apoptosis in several kinds of cell lines. However, the therapeutic effects of LIG on chondrocyte apoptosis remain unknown. In this study, we investigated whether LIG had an anti-apoptotic activity in sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis and could delay cartilage degeneration in a surgically induced rat OA model, and elucidated the potential mechanisms. In vitro studies revealed that LIG significantly suppressed chondrocyte apoptosis and cytoskeletal remodelling, which maintained the nuclear morphology and increased the mitochondrial membrane potential. In terms of SNP, LIG treatment considerably reduced the expression levels of cleaved caspase-3, Bax and inducible nitric oxide synthase and increased the expression level of Bcl-2 in a dose-dependent manner. The LIG-treated groups presented a significantly suppressed expression of activating transcription factor 2 and phosphorylation of Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The inhibitory effect of LIG was enhanced by the p38 MAPK inhibitor SB203580 or the JNK inhibitor SP600125 and offset by the agonist anisomycin. In vivo studies demonstrated that LIG attenuated osteoarthritic cartilage destruction by inhibiting the cartilage chondrocyte apoptosis and suppressing the phosphorylation levels of activating transcription factor 2, JNK and p38 MAPK. This result was confirmed by histological analyses, micro-CT, TUNEL assay and immunohistochemical analyses. Collectively, our studies indicated that LIG protected chondrocytes against SNP-induced apoptosis and delayed articular cartilage degeneration by suppressing JNK and p38 MAPK pathways., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

A series of novel 3-aryl-4-hydroxy-2(5 H ) furanone-acrylate hybrids were designed and synthesized based on the natural butenolides and acrylates scaffolds. The structures of the prepared compounds were characterized by ¹H-NMR, 13 C-NMR and electrospray ionization mass spectrometry (ESI-MS), and the bioactivity of the target compounds against twelve phytopathogenic fungi was investigated. The preliminary in vitro antifungal activity screening showed that most of the target compounds had moderate inhibition on various pathogenic fungi at the concentration of 100 mg·L -1 , and presented broad-spectrum antifungal activities. Further studies also indicated that compounds 7e and 7k still showed some inhibitory activity against Pestallozzia theae , Sclerotinia sclerotiorum and Gibberella zeae on rape plants at lower concentrations, which could be optimized as a secondary lead for further research.

A method aiming at investigating possible bioactive conformations of acyl homoserine lactone (AHL) quorum sensing (QS) modulators is established. The method relies on the exhaustive conformational analysis of AHLs by varying torsion angles around the amide group then on the selection of the closest conformation to those known from co-crystallized XRD data of AHL-receptor complexes. These latter are then docked as rigid ligand within the receptor binding site, leading to interactions with binding site residues which are highly consistent as compared with the data arising from XRD studies. The method is first validated using AHLs for which XRD data of their complexes with their cognate receptor are available, then extended to examples for which the binding mode is still unknown. Three compounds were used to validate the method: hexanoyl homoserine lactone (HHL) as an example of autoinducer, 3-oxo-butanoyl homoserine lactone (OBHL), as a representative model of 3-oxo-AHLs, and 4-(4-chlorophenoxy)butanoyl homoserine lactone (CPOBHL) as an example of a QS inhibitor. The conformational analysis of these three compounds to their cognate protein (TraR, SdiA, LasR and CviR) provides the data which enable the next rigid docking step. Further rigid docking of the closest conformations compared to the known bioactive ones within the binding sites allows to recover the expected binding mode with high precision (atomic RMSD < 2 Å). This "conformational analysis/torsion angle filter/rigid ligand docking" method was then used for investigating three non-natural AHL-type QS inhibitors without known co-crystallized XRD structures, namely was 2-hexenoyl homoserine lactone (HenHL), 3-oxo-4-phenylbutanoyl homoserine lactone (OPBHL) and 3-(4-bromophenyl)propanoyl homoserine lactone (BPPHL). Results provide insights into their possible binding mode by identifying specific interactions with some key residues within the receptor binding site, allowing discussion of their biological activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Derivatives of 2(5 H)-furanone (γ-crotonolactone) are important intermediate synthetic products with a wide range of biological effects that have become widely used in the pharmaceutical industry, medicine, and veterinary medicine, in particular in the prevention and treatment of fish diseases. However, the environmental issue of obtaining these compounds while reducing the negative impact on the surrounding environment remains relevant. This article describes for the first time a method of γ-crotonolactone synthesis that is based on the concept of green chemistry. Synthesis is carried out under mild conditions using nontoxic reagents by furfural oxidation. For the first time, a mixture of hydrogen peroxide and acetic acid was used for the oxidation of furfural in a ratio of 1:0.05. A mixture of organic acids (succinic, maleic, fumaric, formic, and cinnamic acids), obtained as a byproduct in the synthesis of γ-crotonolactone, can be used as a highly effective, ecofriendly organic fertilizer or in a preparation with a stimulating effect.

Bacteria use a cell-cell communication process called quorum sensing to coordinate collective behaviors. Quorum sensing relies on production and group-wide detection of extracellular signal molecules called autoinducers. Here, we probe the activity of the Pseudomonas aeruginosa LasR quorum-sensing receptor using synthetic agonists based on the structure of the native homoserine lactone autoinducer. The synthetic compounds range from low to high potency, and agonist activity tracks with the ability of the agonist to stabilize the LasR protein. Structural analyses of the LasR ligand binding domain complexed with representative synthetic agonists reveal two modes of ligand binding, one mimicking the canonical autoinducer binding arrangement, and the other with the lactone head group rotated approximately 150°. Iterative mutagenesis combined with chemical synthesis reveals the amino acid residues and the chemical moieties, respectively, that are key to enabling each mode of binding. Simultaneous alteration of LasR residues Thr75, Tyr93, and Ala127 converts low-potency compounds into high-potency compounds and converts ligands that are nearly inactive into low-potency compounds. These results show that the LasR binding pocket displays significant flexibility in accommodating different ligands. The ability of LasR to bind ligands in different conformations, and in so doing, alter their potency as agonists, could explain the difficulties that have been encountered in the development of competitive LasR inhibitors.

This study aimed to screen DNA aptamers against the signal molecule C4-HSL of the rhl system for the inhibition of biofilm formation of Pseudomonas aeruginosa using an improved systematic evolution of ligand by exponential enrichment (SELEX) method based on a structure-switching fluorescent activating bead. The aptamers against the C4-HSL with a high affinity and specifity were successfully obtained and evaluated in real-time by this method. Results of biofilm inhibition experiments in vitro showed that the biofilm formation of P. aeruginosa was efficiently reduced to about 1/3 by the aptamers compared with that of the groups without the aptamers. Independent secondary structure simulation and computer-aided tertiary structure prediction (3dRNA) showed that the aptamers contained a highly conserved Y-shaped structural unit. Therefore, this study benefits the search for new methods for the detection and treatment of P. aeruginosa biofilm formation., Competing Interests: The authors have declared that no competing interests exist.

Two new isomeric modified tripeptides, aspergillamides C and D (compounds 1 and 2), together with fifteen known compounds (compounds 3-17), were obtained from the marine sponge-derived fungus Aspergillus terreus SCSIO 41008. The structures of the new compounds, including absolute configurations, were determined by extensive analyses of spectroscopic data (NMR, MS, UV, and IR) and comparisons between the calculated and experimental electronic circular dichroism (ECD) spectra. Butyrolactone I (compound 11) exhibited strong inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with the IC 50 being 5.11 ± 0.53 μmol·L -1 , and acted as a noncompetitive inhibitor based on kinetic analysis., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Background: Flupyradifurone is a member of a novel class of insecticides that possess excellent insecticidal activities. Halogen-containing phenyl groups are important and indispensable structural components of many pesticides. However, replacement of the difluoromethyl group of flupyradifurone with halogen-containing phenyl groups has not been reported. Hence, a series of novel butenolide derivatives containing phenyl groups were synthesized and bioassayed to discover novel compounds with excellent insecticidal activities., Results: Some target molecules exhibited good insecticidal activities against Aphis craccivora. Among the title compounds, 4cc showed the best insecticidal activities with an 50% lethal concentration (LC 50 ) value of 1.72 μg mL -1 , which is superior to that of pymetrozine (LC 50  = 6.86 μg mL -1 ). Molecular docking indicated that 4cc lacks oxidative metabolism by CYP6CM1 and metabolic resistance with imidacloprid. Furthermore, label-free quantitative proteomic analysis indicated that 4cc may be a potential acetylcholine receptor insecticide that acts on the nicotinic acetylcholine receptor. Compound 4cc also decreased the capability for oxidative metabolism, which further supported the molecular docking results., Conclusion: This work can be used to further investigate the mechanism underlying the insecticidal activity of butenolide derivatives and develop potential novel butenolide insecticides. © 2018 Society of Chemical Industry., (© 2018 Society of Chemical Industry.)

N-acyl-l-homoserine lactone (AHL) acylases are a well-known group of enzymes that disrupt quorum sensing in Gram-negative bacteria by degrading AHL signalling molecules. This degradation of signalling molecules (termed 'quorum quenching') has potential uses in the prevention or reduction of biofilm formation and/or bacterial infections. Therefore, there is a great deal of interest in the identification and characterisation of quorum quenching enzymes. Here, we present an optimised fluorescamine-based assay for the detection of AHL acylase activity and demonstrate it can be used in a high-throughput screening format., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Biobased poly(γ-butyrolactone) (PγBL) as a fully biodegradable and bioabsorbable biomaterial has shown superior properties compared to those of other aliphatic polyesters. It is of great importance to prepare amphiphilic block copolymer containing PγBL block to make ordered nano-objects for biomedical applications such as drug delivery systems. However, such an amphiphilic copolymer containing PγBL segment was never successfully prepared mostly due to the synthetic challenges of ring-opening polymerization (ROP) of nonstrained γ-butyrolactone (γBL) monomer. Here, we reported the first preparation of amphiphilic poly(ethylene glycol)- b-poly(γ-butyrolactone) (PEG- b-PγBL) diblock copolymer by using PEG as a macroinitiator. We applied two types of bases to initiate the ROP of γBL. An organic cyclic trimeric phosphazene base (CTPB) was first applied to activate the terminal hydroxyl group of PEG as macroinitiator for ROP of γBL. On the other hand, sodium hydride was used to activate the hydroxyl group of PEG to form sodium alkoxide as an initiating system for ROP of γBL. Both catalytic/initiating system showed moderate control on ROP of γBL and successfully produced PEG- b-PγBL diblock copolymers with varied molecular weights and relatively narrow molecular weight distributions. The effects of catalytic systems, activation temperatures, and monomer concentrations on γBL conversion and molecular weight of PEG- b-PγBL were carefully explored. The thermal properties and phase behaviors of obtained PEG- b-PγBL were also investigated.

In this study, we synthesized four series of novel L-homoserine lactone analogs and evaluated their in vitro quorum sensing (QS) inhibitory activity against two biomonitor strains, Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Studies of the structure-activity relationships of the set of L-homoserine lactone analogs indicated that phenylurea-containing N-dithiocarbamated homoserine lactones are more potent than (Z)-4-bromo-5-(bromomethylene)-2(5H)-furanone (C30), a positive control for biofilm formation. In particular, compared with C30, QS inhibitor 11f significantly reduced the production of virulence factors (pyocyanin, elastase and rhamnolipid), swarming motility, the formation of biofilm and the mRNA level of QS-related genes regulated by the QS system of PAO1. These results reveal 11f as a potential lead compound for developing novel antibacterial quorum sensing inhibitors.

A re-cultivation of the thermophilic fungus Aspergillus terreus TM8, and working up of its extract afforded the dichloro-benzophenone derivative, dihydrogeodin (1) in addition to the butyrolactones I (2), V (3) and VI (4). A literature surveying revealed one recent structural assignment trial for dihydrogeodin (1), however, with some inaccuracies. We report herein a full assignment of dihydrogeodin (1) using extensive study of 1D, 2D NMR and ESI HR mass data. For the first time as well, we report the planar structure of 1 using X-ray crystallography. Docking and molecular dynamic simulation of dihydrogeodin (1) on the isomerase cyclophilin A has revealed its significant potential activity as an antiviral and immunosuppressive agent.

N -acylhomoserine lactones (AHLs), bacterial signaling compounds involved in quorum-sensing, are a structurally diverse group of compounds. We describe here the identification, synthesis, occurrence and biological activity of a new AHL, N -((2 E ,5 Z )-2,5-dodecadienoyl)homoserine lactone ( 11 ) and its isomer N -((3 E ,5 Z )-3,5-dodecadienoyl)homoserine lactone ( 13 ), occurring in several Roseobacter group bacteria (Rhodobacteraceae). The analysis of 26 strains revealed the presence of 11 and 13 in six of them originating from the surface of the macroalgae Fucus spiralis or sediments from the North Sea. In addition, 18 other AHLs were detected in 12 strains. Compound identification was performed by GC/MS. Mass spectral analysis revealed a diunsaturated C 12 homoserine lactone as structural element of the new AHL. Synthesis of three likely candidate compounds, 11 , 13 and N -((2 E ,4 E )-2,4-dodecadienoyl)homoserine lactone ( 5 ), revealed the former to be the natural AHLs. Bioactivity test with quorum-sensing reporter strains showed high activity of all three compounds. Therefore, the configuration and stereochemistry of the double bonds in the acyl chain seemed to be unimportant for the activity, although the chains have largely different shapes, solely the chain length determining activity. In combination with previous results with other Roseobacter group bacteria, we could show that there is wide variance between AHL composition within the strains. Furthermore, no association of certain AHLs with different habitats like macroalgal surfaces or sediment could be detected.

Lignans are polyphenolic compounds with a wide spectrum of biological functions including antioxidant, anti-inflammatory, and anticarcinogenic activities, therefore, there is an increasing interest in promoting the inclusion of lignan-rich foods in humans' diets. Flaxseed is the richest source of the lignan secoisolariciresinol diglucoside-a compound found in the outer fibrous-containing layers of flax. The rumen appears to be the major site for the conversion of secoisolariciresinol diglucoside to the enterolignans enterodiol and enterolactone, but only enterolactone has been detected in milk of dairy cows fed flaxseed products (whole seeds, hulls, meal). However, there is limited information regarding the ruminal microbiota species involved in the metabolism of secoisolariciresinol diglucoside. Likewise, little is known about how dietary manipulation such as varying the nonstructural carbohydrate profile of rations affects milk enterolactone in dairy cows. Our review covers the gastrointestinal tract metabolism of lignans in humans and animals and presents an in-depth assessment of research that have investigated the impacts of flaxseed products on milk enterolactone concentration and animal health. It also addresses the pharmacokinetics of enterolactone consumed through milk, which may have implications to ruminants and humans' health.

Five new oxygenated sesquiterpenes, molestins A⁻D ( 1 , 3 ⁻ 5 ) and epi -gibberodione ( 2 ), three new cyclopentenone derivatives, ent -sinulolides C, D, and F ((+)- 9 ⁻(+)- 11 ), one new butenolide derivative, ent -sinulolide H ((+)- 13 ), and one new cembranolide, molestin E ( 14 ), together with 14 known related metabolites ( 6 ⁻ 8 , (⁻)- 9 ⁻(⁻)- 11 , (±)- 12 , (⁻)- 13 , 15 ⁻ 19 ) were isolated from the Paracel Islands soft coral Sinularia cf. molesta . The structures and absolute configurations were elucidated based on comprehensive spectroscopic analyses, quantum chemical calculations, and comparison with the literature data. Compound 5 is the first example of a norsesquiterpene with a de-isopropyl guaiane skeleton isolated from the genus Sinularia . Molestin E ( 14 ) exhibited cytotoxicities against HeLa and HCT-116 cell lines with IC 50 values of 5.26 and 8.37 μM, respectively. Compounds 4 , 5 , and 8 showed significant inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) with IC 50 values of 218, 344, and 1.24 μM, respectively.

Encouraged by the anti-inflammatory activity of hinokinin in vivo, which is also observed for the analogues dinitrohinokinin and diidrocubebin, herein we used in vitro and in silico methods to assess their selectivity profiles and predict their binding modes with Cyclooxygenases (COX-1 and 2). The in vitro assays demonstrated dinitrohinokinin is about 13 times more selective for COX-2 than for COX-1, a similar profile observed for the drugs celecoxib (selective index ≈9) and meloxicam (selective index ≈11). Predictions of the binding modes suggested dinitrohinokinin interacts with COX-2 very similarly to rofecoxib, exploring residues at the hydrophilic pocket of the enzyme that accessible to ligands only in this isoform. This lignan also interacts with COX-1 in a similar mode to meloxicam, blocking the access of the substrate to the catalytic cleft. Therefore, dinitrohinokinin is a promising lead for the design of selective COX-2 inhibitors., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chemical study on the extract of a marine-derived fungus Aspergillus terreus yielded twelve butenolide derivatives, including three new compounds, namely asperlides A-C (1-3) and nine known butenolides (4-12). The structures of 1-3 were confirmed by comprehensive spectroscopic analysis, including HRESIMS, NMR spectroscopy, and calculated electronic circular dichroism (ECD). The cytotoxicity of the compounds was evaluated using PANC-1, HCC1806, HepG2, BEAS-2B and HT-29 cancer cells. The results showed that (+)-3',3'-di-(dimethylallyl)-butyrolactone II (4) and versicolactone B (6) exhibited the most potent cytotoxin of PANC-1 cell line, with the IC 50 values of 5.3 and 9.4 μM, respectively. Morphological features of apoptosis were observed in 4 and 6-treated PANC-1 cells, including apoptotic body formation, membrane blebbing, cell shrinkage and nuclear condensation. Cell cycle analysis with propidium iodide staining exhibited that 4 inhibits proliferation of PANC-1 cells via the induction of G 2 /M and S phase arrest, while 6 could retard the PANC-1 cells via the induction of S phase arrest. Flow cytometric analysis suggested that treatment with 4 and 6 significantly induced PANC-1 cells apoptosis. These findings indicated that 4 and 6 might serve as a starting point for the development of an anticancer drug for the treatment of pancreatic ductal adenocarcinoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chemical analysis of a marine sponge, Cacospongia sp. (CMB-03404), obtained during deep sea commercial fishing activities off the southern coast of Australia, yielded an unprecedented family of sesterterpene α-methyl-γ-hydroxybutenolides, cacolides A⁻L ( 1 ⁻ 12 ), together with biosynthetically related norsesterterpene carboxylic acids, cacolic acids A⁻C ( 13 ⁻ 15 ). Structures were assigned on the basis of detailed spectroscopic analysis with comparisons to known natural products and biosynthetic considerations. In addition to revealing new chemical diversity, this study provided a valuable platform for comparing and contrasting the capabilities of the traditional dereplication technologies of HPLC-DAD, HPLC-MS and NMR, with those of the emerging HPLC-MS/MS approach known as global natural products social molecular networking (GNPS), as applied to marine sponge sesterterpene tetronic acids.

The analysis of volatiles released by marine Salinispora bacteria uncovered a new class of natural compounds displaying an unusual bicyclic [3.1.0]-lactone skeleton. Although only sub-μg quantities of the compounds were available, the combination of analytical methods, computational spectroscopy, and synthesis allowed unambiguous structural identification of the compounds, called salinilactones, without the need for isolation. Orthogonal hyphenated methods, GC/MS and solid-phase GC/IR allowed to propose a small set of structures consistent with the data. A candidate structure was selected by comparison of DFT-calculated IR spectra and the experimental IR-spectrum. Synthesis confirmed the structure and absolute configuration of three bicyclic lactones, salinilactones A-C. The salinilactones are structurally closely related to the A-factor class of compounds, autoregulators from streptomycete bacteria. They exhibited inhibitory activity against Salinispora and Streptomyces strains., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To investigate structurally novel and anti-neuroinflammatory natural compounds from marine-derived microorganisms, the secondary metabolites of Aspergillus terreus Y10, a fungus separated from the sediment of the coast in the South China Sea, were studied. Three new compounds ( 2 ⁻ 4 ), with novel open-ring butenolide skeletons, were isolated from the ethyl acetate extract of the culture medium. In addition, a typical new butenolide, asperteretal F ( 1 ), was found to dose-dependently inhibit tumor necrosis factor (TNF-α) generation with an IC 50 of 7.6 μg/mL. The present study shows the existence of open-ring butenolides, and suggests that butenolides such as asperteretal F ( 1 ) are a promising new anti-neuroinflammatroy candidate for neurodegenerative diseases.

Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design in situ thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly-(β-butyrolactone-co-lactic acid)-polyethylene glycol-poly (β-butyrolactone-co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring-opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA in situ hydrogels (15%, w/w) were then prepared with drug concentration at 2 mg·mL -1 and the gelation temperatures, rheological properties, in vitro degradation and syringeability of in situ hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA in situ hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96 h, respectively, which was verified by a non-Fickian diffusion mechanism. In vivo ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA in situ hydrogel was higher (AUC was 61.80 μg·mL -1 ·h (p < .01) and t 1/2 was 10.29 h in aqueous humor; AUC was 1008.66 μg·mL -1 ·h (p < .01) and t 1/2 was 13.26 h (p < .01) in vitreous) than GCV injection with extended therapeutic activity. Based on obtained results, it was concluded that the thermosenstive PBLA-PEG-PBLA in situ hydrogel is a promising carrier of GCV for intravitreal injection.

Seven anthraquinones including two new compounds namely capillasterquinones A and B (1 and 2) and one new butenolide namely capillasterolide (8) were isolated and structurally elucidated from the crinoid Capillaster multiradiatus. The inhibitory effect of compounds 1-8 on lipopolysaccharide (LPS)-induced nitric oxide (NO) production as well as inhibition of 1 on expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) proteins in RAW264.7 cells were also evaluated. As the obtained results, capillasterquinone A (1) showed strong NO production inhibitory activity with an IC 50 of 5.89±0.11 µM. In addition, compound 1 reduced the LPS-induced iNOS and COX-2 expressions in a dose-dependent manner.

Flupyradifurone (FPD), a member of the new class of butenolide insecticides, acts on nicotinic acetylcholine receptors. Studies on genotoxic and carcinogenic effects of FPD are very limited. This is the first study to investigate the cytotoxic and genotoxic effects of FPD and its metabolites on human lymphocyte cultures with or without a metabolic activation system (S9 mix) using chromosomal aberration (CA) and micronucleus (MN) tests. The cultures were treated with 85, 170, and 340 µg/ml of FPD in the presence (3 h treatment) and absence (48 h treatment) of S9 mix. Dimethyl sulfoxide (DMSO) was used as a solvent control. Statistically significant decreases were detected at the medium and highest concentrations for 48 h treatments while decreases in mitotic index (MI) in the presence of the S9 mix were found statistically significant at all FPD concentrations tested when compared with the solvent control. FPD also decreased the nuclear division index (NDI) at the highest concentration (340 µg/ml) in the absence of S9 mix. When compared with the solvent control, increases in CA frequencies were significant at the medium and highest concentrations. Significantly increased MN frequency was only found at the highest FPD concentration in cultures without S9 mix compared with the solvent control while increases in the MN frequencies in the presence of S9 mix were statistically significant at all FPD concentrations. The results of the present study indicate that FPD and its metabolites can show cytotoxic and genotoxic effects in human lymphocytes. More genotoxicity studies are necessary to make a possible risk assessment in humans.

Certain bacteria can coordinate group behaviors via a chemical communication system known as quorum sensing (QS). Gram-negative bacteria typically use N-acyl l-homoserine lactone (AHL) signals and their cognate intracellular LuxR-type receptors for QS. The opportunistic pathogen Pseudomonas aeruginosa has a relatively complex QS circuit in which two of its LuxR-type receptors, LasR and QscR, are activated by the same natural signal, N-(3-oxo)-dodecanoyl l-homoserine lactone. Intriguingly, once active, LasR activates virulence pathways in P. aeruginosa, while activated QscR can inactivate LasR and thus repress virulence. We have a limited understanding of the structural features of AHLs that engender either agonistic activity in both receptors or receptor-selective activity. Compounds with the latter activity profile could prove especially useful tools to tease out the roles of these two receptors in virulence regulation. A small collection of AHL analogs was assembled and screened in cell-based reporter assays for activity in both LasR and QscR. We identified several structural motifs that bias ligand activation towards each of the two receptors. These findings will inform the development of new synthetic ligands for LasR and QscR with improved potencies and selectivities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

An ab initio simulation scheme is introduced as a theoretical prescreening approach to facilitate and enhance the research for pH-sensitive biomarkers. The proton 1 H and carbon 13 C nuclear magnetic resonance (NMR) chemical shifts of the recently published marker for extracellular pH, [1,5- 13 C 2 ]zymonic acid (ZA), and the as yet unpublished ( Z)-4-methyl-2-oxopent-3-enedioic acid (OMPD) were calculated with ab initio methods as a function of the pH. The influence of the aqueous solvent was taken into account either by an implicit solvent model or by explicit water molecules, where the latter improved the accuracy of the calculated chemical shifts considerably. The theoretically predicted chemical shifts allowed for a reliable NMR peak assignment. The p K a value of the first deprotonation of ZA and OMPD was simulated successfully whereas the parametrization of the implicit solvent model does not allow for an accurate description of the second p K a . The theoretical models reproduce the pH-induced chemical shift changes and the first p K a with sufficient accuracy to establish the ab initio prescreening approach as a valuable support to guide the experimental search for pH-sensitive biomarkers.

The ketone body ester (R)-3-hydroxybutyryl-(R)-3-hydroxybutyrate and its (S,S) enantiomer were prepared in a short, operationally simple synthetic sequence from racemic β-butyrolactone. Enantioselective hydrolysis of β-butyrolactone with immobilized Candida antarctica lipase-B (CAL-B) results in (R)-β-butyrolactone and (S)-β-hydroxybutyric acid, which are easily converted to (R) or (S)-ethyl-3-hydroxybutyrate and reduced to (R) or (S)-1,3 butanediol. Either enantiomer of ethyl-3-hydroxybutyrate and 1,3 butanediol are then coupled, again using CAL-B, to produce the ketone body ester product. This is an efficient, scalable, atom-economic, chromatography-free, and low cost synthetic method to produce the ketone body esters., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pseudomonas aeruginosa is an opportunistic pathogen that coordinates the production of many virulence phenotypes at high population density via quorum sensing (QS). The LuxR-type receptor RhlR plays an important role in the P. aeruginosa QS process, and there is considerable interest in the development of chemical approaches to modulate the activity of this protein. RhlR is activated by a simple, low molecular weight N-acyl l-homoserine lactone signal, N-butanoyll-homoserine lactone (BHL). Despite the emerging prominence of RhlR in QS pathways, there has been limited exploration of the chemical features of the BHL scaffold that are critical to its function. In the current study, we sought to systematically delineate the structure-activity relationships (SARs) driving BHL activity for the first time. A focused library of BHL analogues was designed, synthesized, and evaluated in cell-based reporter gene assays for RhlR agonism and antagonism. These investigations allowed us to define a series of SARs for BHL-type ligands and identify structural motifs critical for both activation and inhibition of the RhlR receptor. Notably, we identified agonists that have ∼10-fold higher potencies in RhlR relative to BHL, are highly selective for RhlR agonism over LasR, and are active in the P. aeruginosa background. These compounds and the SARs reported herein should pave a route toward new chemical strategies to study RhlR in P. aeruginosa.

The synthesis of densely functionalized trisubstituted and tetrasubstituted furans via a novel Ru(II)-catalyzed intramolecular cyclization of vinyl diazoesters is reported. The synthetic utility of these furans is further demonstrated through a simple acid-mediated reaction to access highly substituted Δα,β-butenolides.

The synthesis of β-lactones from epoxides through ring-expanding carbonylation using homogeneous catalysts has received much attention. However, homogeneous catalysts suffer from difficulty in product separation and recycling of the catalyst, limiting their industrial usage. Herein, a novel heterogeneous catalyst, [Cr-metalated porous porphyrin polymer] + [Co(CO) 4 ] - , was prepared and used for the conversion of propylene oxide (PO) to β-butyrolactone; this catalyst presented superior catalytic activity and selectivity (99%) than our previous heterogeneous catalyst. In addition, the catalyst was readily separated from the product without significant loss of catalytic activity. A possible method to recover the original catalytic activity also was demonstrated.

Two novel γ-lactone derivatives, trigoheterophines A (1) and B (2), together with four known furan derivatives (3-6), were isolated from the stems and leaves of Trigonostemon heterophyllus. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A (1) and B (2) represent an unusual type of γ-lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds (3-6) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-6 showed significant antiproliferative effects against various human cancer cell lines with IC 50 values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ-lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Five N-acyl homoserine lactone-degrading bacteria (quorum quenching (QQ) strains) were selected to evaluate their impacts on growth, virulence factors and biofilm formation in Yersinia ruckeri in vitro. No difference was observed among the growth pattern of Y. ruckeri in monoculture and coculture with the QQ strains. To investigate the regulation of virulence factors by quorum sensing in Y. ruckeri, cultures were supplemented with 3oxo-C8-HSL. The results indicated that swimming motility and biofilm formation are positively regulated by QS (p < 0.05), whereas caseinase, phospholipase and haemolysin productions are not influenced by 3oxo-C8-HSL (p > 0.05). The QQs were able to decrease swimming motility and biofilm formation in Y. ruckeri. QQ bacteria were supplemented to trout feed at 10 8  CFU/g (for 40 days). Their probiotic effect was verified by Y. ruckeri challenge either by immersion or injection in trout. All strains could significantly increase fish survival with Bacillus thuringiensis and Citrobacter gillenii showing the highest and lowest relative percentage survival (RPS) values (respectively, 85% and 38%). Besides, there was no difference between the RPS values by either immersion or injection challenge expect for B. thuringiensis. The putative involvement of the QQ capacity in the protection against Yersinia is discussed., (© 2018 John Wiley & Sons Ltd.)

We report a Zn-ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Reductive metabolism of strigolactones (SLs) in several plants was investigated. Analysis of aquaculture filtrates of cowpea and sorghum each fed with four stereoisomers of GR24, the most widely used synthetic SL, revealed stereospecific reduction of the double bond at C-3' and C-4' in the butenolide D-ring with preference for an unnatural 2'S configuration. The cowpea metabolite converted from 2'-epi-GR24 and the sorghum metabolite converted from ent-GR24 had the methyl group at C-4' in the trans configuration with the substituent at C-2', different from the cis configuration of the synthetic H 2 -GR24 reduced with Pd/C catalyst. The plants also reduced the double bond in the D-ring of 5-deoxystrigol isomers with a similar preference. The metabolites and synthetic H 2 -GR24 stereoisomers were much less active than were the GR24 stereoisomers in inducing seed germination of the root parasitic weeds Striga hermonthica, Orobanche crenata, and O. minor. These results provide additional evidence of the importance of the D-ring for bioactivity of SLs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)