658 results on '"Castanospermine"'
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2. Animal Cell Expression Systems
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Butler, M., Reichl, U., Scheper, Thomas, Series Editor, Belkin, Shimshon, Editorial Board Member, Bley, Thomas, Editorial Board Member, Bohlmann, Jörg, Editorial Board Member, Gu, Man Bock, Editorial Board Member, Hu, Wei-Shou, Editorial Board Member, Mattiasson, Bo, Editorial Board Member, Olsson, Lisbeth, Editorial Board Member, Seitz, Harald, Editorial Board Member, Silva, Ana Catarina, Editorial Board Member, Ulber, Roland, Editorial Board Member, Zeng, An-Ping, Editorial Board Member, Zhong, Jian-Jiang, Editorial Board Member, Zhou, Weichang, Editorial Board Member, Rapp, Erdmann, editor, Reichl, Udo, editor, Alagesan, K., With Contri.By, Betenbaugh, M. J., With Contri.By, Butler, M., With Contri.By, Buyel, J. F., With Contri.By, Cajic, S., With Contri.By, Callewaert, N., With Contri.By, Can, Ö., With Contri.By, Cox, M. M. J., With Contri.By, DeLisa, M. P., With Contri.By, De Wachter, C., With Contri.By, Elling, L., With Contri.By, Fischer, R., With Contri.By, Flitsch, S. L., With Contri.By, Frohnmeyer, H., With Contri.By, Gottschalk, J., With Contri.By, Goyette-Desjardins, G., With Contri.By, Heffner, K. M., With Contri.By, Hizal, D. B., With Contri.By, Hoffmann, M., With Contri.By, Holland, T., With Contri.By, Jefferis, R., With Contri.By, Kolarich, D., With Contri.By, Laaf, D., With Contri.By, Lepenies, B., With Contri.By, Malik, A., With Contri.By, Martinez, J. E. R., With Contri.By, Mills, D. C., With Contri.By, Moeller, T. D., With Contri.By, Palomares, L. A., With Contri.By, Pralow, A., With Contri.By, RamÚrez, O. T., With Contri.By, Rapp, E., With Contri.By, Reichl, U., With Contri.By, Rexer, T., With Contri.By, Sack, M., With Contri.By, Schillberg, S., With Contri.By, Schön, K., With Contri.By, Seeberger, P. H., With Contri.By, Srivastava, I. K., With Contri.By, Stoger, E., With Contri.By, Thomas, B., With Contri.By, Twyman, R. M., With Contri.By, Van Landuyt, L., With Contri.By, Varón Silva, D., With Contri.By, Wang, Q., With Contri.By, Weyant, K. B., With Contri.By, and Yates, L. E., With Contri.By
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- 2021
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3. Recent Developments in the Synthesis of Polyhydroxylated Indolizidines.
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Fraňová, Paula and Marchalín, Štefan
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INDOLIZIDINES synthesis , *GLYCOSIDASE inhibitors , *GLYCOSIDASES , *INDOLIZIDINES , *VIRUS diseases , *SWAINSONINE - Abstract
Since their discovery, polyhydroxylated indolizidines have been the focus of attention for both biologists and synthetic chemists. They are classified as iminosugar alkaloids: nitrogen‐based carbohydrate mimetics that are potent inhibitors of glycosidases. Many discovered glycosidase inhibitors were found to possess biological activity, and they are therefore considered to be potential therapeutics in the treatment of various diseases such as viral infections, diabetes, or cancer. Not surprisingly, the interest in the preparation of these substances has been enormous. This review presents the latest developments in the synthesis of naturally occurring polyhydroxylated indolizidines and their synthetic enantiomers. In addition, the synthesis of several novel polyhydroxylated indolizidines, which were discovered to have inhibitory activity, is reported. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Castanospermine suppresses CD44 ectodomain cleavage as revealed by transmembrane bioluminescent sensors.
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Natsumi Noda and Takeaki Ozawa
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CD44 antigen , *LUCIFERASES , *CANCER cell migration , *DETECTORS , *EXTRACELLULAR matrix , *ALPHA-glucosidases - Abstract
Cluster of differentiation 44 (CD44) is a single-pass transmembrane glycoprotein that is a widely distributed cell-surface adhesion molecule. CD44 undergoes ectodomain cleavage by membrane-associated metalloproteinases in breast cancer cells. Cleavage plays a critical role in cancer cell migration by mediating the interaction between CD44 and the extracellular matrix. To explore inhibitors of CD44 ectodomain cleavage, we developed two bioluminescent sensors for the detection of CD44 ectodomain cleavage. The sensors were designed as two-transmembrane proteins with split-luciferase fragments, one of which was cyclized by protein trans-splicing of a DnaE intein. These two sensors emit light by the cyclization or the spontaneous complementation of the luciferase fragments. The luminescence intensities decreased upon cleavage of the ectodomain in breast cancer cells. The sensors revealed that castanospermine, an α-glucosidase inhibitor, suppressed the ectodomain cleavage of endogenous CD44 in breast cancer cells. Castanospermine also inhibited breast cancer cell invasion. Thus, the sensors are beneficial tools for evaluating the effects of different inhibitors. [ABSTRACT FROM AUTHOR]
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- 2022
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5. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication.
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Clarke, Elizabeth C, Nofchissey, Robert A, Ye, Chunyan, and Bradfute, Steven B
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SARS-CoV-2 , *IMINOSUGARS , *VIRAL proteins , *VIRUS diseases , *ALPHA-glucosidases , *VIRAL replication - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Natural Products Database Screening for the Discovery of Naturally Occurring SARS‐Cov‐2 Spike Glycoprotein Blockers.
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Al‐Sehemi, Abdullah G., Olotu, Fisayo A., Dev, Sanal, Pannipara, Mehboobali, Soliman, Mahmoud E., Carradori, Simone, and Mathew, Bijo
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SARS-CoV-2 , *NATURAL products , *COVID-19 , *PANDEMICS - Abstract
SARS‐CoV‐2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best‐in‐class derivatives in silico able to target an essential structure of the virus and to act in the early stage of infection. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Epitope Shaving Promotes Fungal Immune Evasion
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Delma S. Childers, Gabriela Mol Avelar, Judith M. Bain, Arnab Pradhan, Daniel E. Larcombe, Mihai G. Netea, Lars P. Erwig, Neil A. R. Gow, and Alistair J. P. Brown
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Candida albicans ,cell wall ,Xog1 exoglucanase ,β-glucan shaving ,immune evasion ,castanospermine ,Microbiology ,QR1-502 - Abstract
ABSTRACT The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes. IMPORTANCE The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.
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- 2020
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8. Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro
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Gitanjali Bhushan, Levina Lim, Ian Bird, Shubhada K. Chothe, Ruth H. Nissly, and Suresh V. Kuchipudi
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Zika virus ,antiviral ,iminosugar ,ER-AGI ,castanospermine ,celgosivir ,Microbiology ,QR1-502 - Abstract
Zika virus (ZIKV), a vector-borne virus of the family Flaviviridae, continues to spread and remains a significant global public health threat. Currently, there are no approved vaccines or antivirals against ZIKV. We investigated the anti-ZIKV ability of three iminosugars with endoplasmic reticulum α-glucosidase inhibitor (ER-AGI) activity, namely deoxynojirimycin (DNJ), castanospermine, and celgosivir. None of the three iminosugars showed any significant cytotoxicity in Vero or human microglia CHME3 cells when applied for 72 h at concentrations up to 100 μM. Iminosugar treatment of Vero or CHME3 cells prior to ZIKV infection resulted in significant inhibition of ZIKV replication over 48 h. Reduction in ZIKV replication in iminosugar-treated cells was not associated with any significant change in the expression levels of key antiviral genes. Following infection with three different strains of ZIKV, iminosugar-treated Vero or CHME3 cells showed no cell death, whereas vehicle-treated control cells exhibited 50–60% cell death at 72 h post-infection (hpi). While there was no significant difference in apoptosis between iminosugar-treated and control cells, iminosugar-treated cells exhibited a substantial reduction of necrosis at 72 hpi following ZIKV infection. In summary, iminosugars with ER-AGI activity inhibit ZIKV replication and significantly reduce necrosis without altering the antiviral gene expression and apoptosis of infected human cells. The results of this study strongly suggest that iminosugars are promising anti-ZIKV antiviral agents and such warrant further in vivo studies.
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- 2020
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9. Microwave-Assisted Synthesis of Andrographolide Analogues as Potent β-Glycosidase Inhibitors
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Masood ur Rahman, Iram Ayoob, Shakeel u Rehman, Khursheed A. Bhat, and Tabassum Ara
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andrographolide ,β-glucosidase ,sweet almond ,castanospermine ,Chemistry ,QD1-999 - Abstract
Abstract Andrographolide, a bioactive compound isolated from Andrographis paniculata exhibits multiple pharmacological activities, including anti-HIV, antiplatelet aggregation, hepatic lipid peroxidation protective, hepatoprotective, choleretic, and anticancer effects. Herein, we report the synthesis of diverse analogues of andrographolide along with their β-glucosidase inhibitory activity against sweet almond β-glucosidase. The parent compound, And-1, displayed moderate inhibitory activity against the sweet almond β-glucosidase with IC50 of 142.5 μM. Among the synthesised analogues And-10 showed the best activity, with IC50 of 92.4 μM, whereas the oxidised products (And-4 and And-5) were moderately active against the tested enzyme. Additionally, compounds And-6, And-7, And-8, and And-10 exhibited better β-glucosidase inhibitory activity than the positive control Castanospermine, with IC50 of 100.2, 102.4, 106.5, and 92.4 μM, respectively. These results highlight the importance of an electron-withdrawing NO2 group on the phenyl moiety in attaining the better β-glucosidase inhibition. It is noteworthy that the effect of a particular group plays a significant role in bioactivity. This study thus highlights an important aspect with regard to the most active compounds, which could extend the arsenal of compounds affecting the corresponding enzymes after further polishing and fine tuning.
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- 2018
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10. A "turn off-on" fluorescent nanoprobe consisting of CuInS2 quantum dots for determination of the activity of β-glucosidase and for inhibitor screening.
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Liu, Ziping, Tian, Ye, Han, Yang, Bai, Edith, Li, Yanan, Xu, Zhiwei, and Liu, Shasha
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QUANTUM dots , *THIOUREA , *FLUORESCENT probes , *SOIL sampling , *DETECTION limit , *CYANIDES - Abstract
A fluorescent "turn off-on" nanoprobe is described for highly sensitive and selective determination of the activity of the enzyme β-glucosidase (β-Glu). Firstly, cysteine modified CuInS2 quantum dots (Cys-CuInS2 QDs) were prepared from indium(III) and copper(II) salts and the presence of thiourea. The red fluorescence of the Cys-CuInS2 QDs, with excitation/emission maxima at 590/656 nm, is quenched by Cu(II). However, in the presence of β-Glu and the cyanogenic glycoside, enzymatic hydrolysis leads to the formation of cyanide. The latter competitively binds to Cu(II) owing to its high affinity for cyanide. This restores the fluorescence of the Cys-CuInS2 QDs. Under the optimum conditions, fluorescence increases linearly in the 0.5–700 U·L−1 β-Glu activity range. The detection limit is 0.2 U·L−1. The nanoprobe was applied to analyze spiked soil samples, and satisfactory results were obtained. The average recoveries of β-Glu were in the range of 96–103%, and the RSD was lower than 4.0%. The fluorescent probe can also be used to screen for β-Glu inhibitors as demonstrated for castanospermine as an example. [ABSTRACT FROM AUTHOR]
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- 2019
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11. A novel approach to the synthesis of polyhydroxylated indolizidine alkaloids
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Farrant, Elizabeth
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547 ,Castanospermine ,Chiral pyrrolidines - Published
- 1997
12. Capillary electrophoresis-based online immobilized enzyme reactor for beta-glucosidase kinetics assays and inhibitors screening.
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Wu, Zhao-Yu, Zhang, Hao, Li, Qiao-Qiao, Yang, Feng-Qing, and Li, De-Qiang
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CAPILLARY electrophoresis , *IMMOBILIZED enzymes , *BETA-glucosidase genetics , *ENZYME kinetics , *CASTANOSPERMINE , *MICHAELIS-Menten mechanism - Abstract
Abstract A capillary electrophoresis (CE)-based beta-glucosidase (beta-Glu) immobilized enzyme microreactor (IMER) was constructed for enzyme kinetics study and inhibitor screening with the aid of polydopamine coating. The enzyme kinetic and inhibition studies of beta-Glu were comprehensively evaluated using p -nitrophenyl beta- d -glucopyranoside as a model substrate and castanospermine as a model inhibitor. The Michaelis-Menten constant value of the immobilized beta-Glu in the developed IMER was calculated to be 2.79 mmol/L. The half-maximal inhibitory concentration and inhibition constant of castanospermine were 13.22 μg/mL and 1.54 μg/mL, respectively. In addition, after 50 consecutive runs, the IMER activity was remained at 89.5% of the initial immobilized beta-Glu activity, which showed that the constructed IMER has good stability and repeatability. Finally, the developed method was successfully applied to screen beta-Glu inhibitors from twelve flavonoids. Four flavonoids include genistein, baicalein, epicatechin gallate and epigallocatechin gallate had significant inhibitory effect on beta-Glu, and their binding mode with enzyme was further verified via the molecular docking analysis. In summary, the developed CE based beta-Glu-IMER is a reliable method for screening beta-Glu inhibitors from natural products. Highlights • A stable and reliable online CE-based beta-Glu-IMER was firstly constructed. • The prepared IMER was successfully applied to screen beta-Glu inhibitors. • Four flavonoids were discovered as new inhibitors targeting beta-Glu. • The enzyme-inhibitor binding mode was further verified by molecular docking. [ABSTRACT FROM AUTHOR]
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- 2019
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13. Gene Cloning, Prokaryotic Expression, and Biochemical Characterization of a Soluble Trehalase in Helicoverpa armigera Hübner (Lepidoptera: Noctuidae).
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Dong Ai, Shenhang Cheng, Hetan Chang, Ting Yang, Guirong Wang, and Caihong Yu
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TREHALASE , *DISACCHARIDASES , *MOLECULAR cloning , *MOLECULAR genetics , *PATHOGENIC microorganisms - Abstract
Trehalase is an indispensable component of insect hemolymph that plays important role in energy metabolism and stress resistance. In this study, we cloned and expressed the gene encoding soluble trehalase (HaTreh-1) of Helicoverpa armigera (cotton bollworm) and characterized the enzyme. HaTreh-1 had a full-length open reading frame encoding a protein of 571 amino acids. Sequence comparison indicated that HaTreh-1 was similar to some known insect trehalases. Two essential active sites (D321 and E519) and three essential residues (R168, R221, and R286) were conserved in HaTreh-1. The recombinant trehalase was expressed in Escherichia coli and purified by nickel exchange chromatography. Molecular weight of the recombinant protein was about 71 kDa, and the optimum HaTreh-1 enzyme activity is at 55°C with pH 6.0. Enzymatic assays showed a Km value of 72.8 mmol/liter and a Vmax value of 0.608 mmol/(liter·min). Inhibition assays in vitro indicated that castanospermine, a polyhydroxylated alkaloid, was an effective competitive inhibitor of trehalase with a Ki value of 6.7 μmol/liter. The inhibitor action of castanospermine was linked to its modification effect on trehalase structure. The circular dichroism spectrum showed that the percentage of α-helix increased under the presence of castanospermine. Results of our study will aid in developing effective trehalase inhibitors for controlling H. armigera in the future. [ABSTRACT FROM AUTHOR]
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- 2018
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14. IAA-glucopyranoside stimulation of corn coleoptiles elongation
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Adriana Szmidt-Jaworska, Jacek Kęsy, and Jan Kopcewicz
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Bound auxins ,IAA-glucopyranoside ,corn coleoptiles ,castanospermine ,Botany ,QK1-989 - Abstract
It has been previously suggested that 1-O-IAGIuc growth stimulation occurs as the effect of its hydrolysis into a free IAA. In present experiments castanospermine, a known β-glucosidase inhibitor, was included. 1-O-IAGluc in the presence of castanospermine stimulated growth of corn coleoptiles segments even stronger then free IAA. So, it seems that 1-O-IAGluc itself, is responsible for the observed stimulation of corn coleoptile segments elongation.
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- 2014
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15. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication
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Elizabeth C. Clarke, Robert A. Nofchissey, Chunyan Ye, and Steven B. Bradfute
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1-Deoxynojirimycin ,AcademicSubjects/SCI01000 ,iminosugar ,viruses ,Iminosugar ,virus ,Virus Replication ,Biochemistry ,Celgosivir ,03 medical and health sciences ,chemistry.chemical_compound ,celgosivir ,Viral entry ,Calnexin ,Chlorocebus aethiops ,Animals ,Humans ,Glycoside Hydrolase Inhibitors ,Vero Cells ,030304 developmental biology ,0303 health sciences ,SARS-CoV-2 ,030306 microbiology ,Communication ,Indolizines ,COVID-19 ,UV-4 ,Virology ,COVID-19 Drug Treatment ,castanospermine ,Viral replication ,Castanospermine ,chemistry ,Cell culture ,Vero cell - Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.
- Published
- 2020
16. Virtual screening to identify novel potential inhibitors for Glutamine synthetase of Mycobacterium tuberculosis
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Madhulata Kumari and Naidu Subbarao
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chemistry.chemical_classification ,Virtual screening ,Natural product ,biology ,General Medicine ,biology.organism_classification ,Mycobacterium tuberculosis ,chemistry.chemical_compound ,Enzyme ,chemistry ,Castanospermine ,Biochemistry ,Structural Biology ,Docking (molecular) ,Glutamine synthetase ,Salt bridge ,Molecular Biology - Abstract
Glutamine synthetase (GS) of Mycobacterium tuberculosis (Mtb) is an essential enzyme which is involved in nitrogen metabolism and cell wall synthesis. It is involved in the inhibition of phagosome-lysosome fusion by preventing acidification. Targeting GS can be helpful to control the infection of Mtb. In order to identify potential inhibitors, we screened chemical libraries (56,400 compounds of ChEMBL anti-mycobacterial, 1596 FDA approved drugs, 419 Natural product and 916 phytochemical) against this target using the virtual screening approach. Screening by molecular docking identified ten top-ranked compounds as GSMtb inhibitors and they were compared with known inhibitors (as control). Since GS enzyme (GSHs) is also present in human. We have compared the protein sequence of GS from Mtb and human using the P-BLAST in NCBI. We found ∼27% identity in between these two sequences, so we also compared the binding affinity of inhibitor between Mtb and human. Finally, we identified top two compounds namely CHEMBL387509, CHEMBL226198 from ChEMBL anti-mycobacterial dataset, and Eriocitrin and Malvidin from phytochemical dataset which showed lees binding affinity towards GSHs whereas Pamidronate, and Phentermine from FDA approved drugs and (-)-Quinic Acid, Hexopyranuronic acid, Quebrachit, and Castanospermine from natural product showed protein-ligand interaction with Mtb protein while no interaction with GSHs. The top two docked complexes were subjected to molecular dynamic simulation to understand the stability of the molecule. Further, we calculated the binding free energy of the docked complex and analyzed hydrogen bond, salt bridge, pie stacking, and hydrophobic interaction in the docking region. These ligands exhibited very good binding affinity GSMtb enzymes. Therefore, these ligands are novel and drug-likeness compounds, and they may be potential inhibitors of M tuberculosis.Communicated by Ramaswamy H. Sarma.
- Published
- 2019
17. Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis.
- Author
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Hong, Yu-pu, Chen, Chen, Guo, Wen-yi, Zhao, Liang, Mei, Fang-chao, Xiang, Ming-wei, and Wang, Wei-xing
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CASTANOSPERMINE , *DRUG efficacy , *PANCREATITIS treatment , *INFLAMMATION , *LABORATORY rats - Abstract
Background and Aims Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response. Castanospermine (CAST) is an alkaloid from the Castanospermum australe, known as an anti-inflammatory agent and immunosuppressant in animal experiments. However, whether CAST can attenuate AP remains unclear. This study investigated the effects of CAST on sodium taurocholate (STC)-induced severe acute pancreatitis (SAP) in rats and the pertinent mechanism. Methods SAP was induced in rats by a retrograde infusion of 5% STC (1 mL/kg) into the biliopancreatic duct. CAST (10, 50, 100, 200 and 500 mg/kg body weight) was then administered via intraperitoneal injection. Measurement of serum amylase, lipase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen and pancreas pathological grading was used to estimate the severity of pancreatitis. Serum levels of interleukin (IL) -1β, IL-6 and IL-10 were studied by enzyme-linked immunosorbent assay (ELISA). Nuclear factor (NF) -κB, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression in pancreas was evaluated by immunohistochemistry. Results Administration of CAST following SAP was found to ameliorate the acute pancreatic tissue injury and exhibit a more appropriately protective effect at the dose of 200 mg/kg body weight. In addition, it decreased the interleukin production in serum and NF-κB activation, TNF-α, ICAM-1 and VCAM-1 up-regulation in pancreatic tissue. Conclusions Our study demonstrated that CAST exerts a protective effect on SAP in rats. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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18. Contribution to the synthesis of polyhydroxylated indolizidines starting from sugar isothiocyanates.
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Elečko, Ján, Gonda, Jozef, Martinková, Miroslava, and Vilková, Mária
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INDOLIZIDINES synthesis , *SUGAR , *ISOTHIOCYANATES , *CASTANOSPERMINE , *METATHESIS reactions , *AMINATION - Abstract
A straightforward stereoselective route towards castanospermine analogues starting from the corresponding d - gluco - and l - ido -hexofuranose isothiocyanates (5 S )- 2 and (5 R )- 2 is described. The key transformations of this approach rely on ring-closing metathesis and reductive amination to form the final polyhydroxylated indolizidines 10 – 13 in good overall yields. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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19. A yeast strain associated to Anopheles mosquitoes produces a toxin able to kill malaria parasites.
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Valzano, Matteo, Cecarini, Valentina, Cappelli, Alessia, Capone, Aida, Bozic, Jovana, Cuccioloni, Massimiliano, Epis, Sara, Petrelli, Dezemona, Angeletti, Mauro, Eleuteri, Anna Maria, Favia, Guido, and Ricci, Irene
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MALARIA treatment , *YEAST , *ANOPHELES stephensi , *PLASMODIUM vivax , *MICROSCOPY , *CASTANOSPERMINE , *THERAPEUTICS - Abstract
Background: Malaria control strategies are focusing on new approaches, such as the symbiotic control, which consists in the use of microbial symbionts to prevent parasite development in the mosquito gut and to block the transmission of the infection to humans. Several microbes, bacteria and fungi, have been proposed for malaria or other mosquito-borne diseases control strategies. Among these, the yeast Wickerhamomyces anomalus has been recently isolated from the gut of Anopheles mosquitoes, where it releases a natural antimicrobial toxin. Interestingly, many environmental strains of W. anomalus exert a wide anti-bacterial/fungal activity and some of these 'killer' yeasts are already used in industrial applications as food and feed bio-preservation agents. Since a few studies showed that W. anomalus killer strains have antimicrobial effects also against protozoan parasites, the possible anti-plasmodial activity of the yeast was investigated. Methods: A yeast killer toxin (KT), purified through combined chromatographic techniques from a W. anomalus strain isolated from the malaria vector Anopheles stephensi, was tested as an effector molecule to target the sporogonic stages of the rodent malaria parasite Plasmodium berghei, in vitro. Giemsa staining was used to detect morphological damages in zygotes/ookinetes after treatment with the KT. Furthermore, the possible mechanism of action of the KT was investigated pre-incubating the protein with castanospermine, an inhibitor of β-glucanase activity. Results: A strong anti-plasmodial effect was observed when the P. berghei sporogonic stages were treated with KT, obtaining an inhibition percentage up to around 90 %. Microscopy analysis revealed several ookinete alterations at morphological and structural level, suggesting the direct implication of the KT-enzymatic activity. Moreover, evidences of the reduction of KT activity upon treatment with castanospermine propose a β-glucanase-mediated activity. Conclusion: The results showed the in vitro killing efficacy of a protein produced by a mosquito strain of W. anomalus against malaria parasites. Further studies are required to test the KT activity against the sporogonic stages in vivo, nevertheless this work opens new perspectives for the possible use of killer strains in innovative strategies to impede the development of the malaria parasite in mosquito vectors by the means of microbial symbionts. [ABSTRACT FROM AUTHOR]
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- 2016
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20. The Lysozyme Inhibitor Thionine Acetate Is Also an Inhibitor of the Soluble Lytic Transglycosylase Slt35 from Escherichia coli
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Andrew C. Wood, Aysha B. Mezoughi, Sarah Elizabeth Adams, E. Joel Loveridge, Gregor M. Parker, Richard B. Sessions, Alan Scott, Chiara M. Costanzo, and Enas M. Behiry
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0301 basic medicine ,030106 microbiology ,Pharmaceutical Science ,Organic chemistry ,medicine.disease_cause ,Thionine ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,QD241-441 ,Drug Discovery ,medicine ,Glycoside hydrolase ,Physical and Theoretical Chemistry ,Escherichia coli ,enzyme inhibition ,chemistry.chemical_classification ,biology ,Active site ,antibacterial ,030104 developmental biology ,Enzyme ,Biochemistry ,Lytic cycle ,chemistry ,Castanospermine ,Chemistry (miscellaneous) ,biology.protein ,thionine acetate ,Molecular Medicine ,lytic transglycosylase ,Lysozyme - Abstract
Lytic transglycosylases such as Slt35 from E. coli are enzymes involved in bacterial cell wall remodelling and recycling, which represent potential targets for novel antibacterial agents. Here, we investigated a series of known glycosidase inhibitors for their ability to inhibit Slt35. While glycosidase inhibitors such as 1-deoxynojirimycin, castanospermine, thiamet G and miglitol had no effect, the phenothiazinium dye thionine acetate was found to be a weak inhibitor. IC50 values and binding constants for thionine acetate were similar for Slt35 and the hen egg white lysozyme. Molecular docking simulations suggest that thionine binds to the active site of both Slt35 and lysozyme, although it does not make direct interactions with the side-chain of the catalytic Asp and Glu residues as might be expected based on other inhibitors. Thionine acetate also increased the potency of the beta-lactam antibiotic ampicillin against a laboratory strain of E. coli.
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- 2021
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21. Stereoselective allylation reactions of acyclic and chiral α-amino-β-hydroxy aldehydes 3: Total synthesis of (+)-1-epi-castanospermine
- Author
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Won-Hun Ham and In-Soo Myeong
- Subjects
010405 organic chemistry ,Stereochemistry ,organic chemicals ,Organic Chemistry ,food and beverages ,Total synthesis ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,Castanospermine ,chemistry ,Drug Discovery ,Stereoselectivity - Abstract
Stereoselective allylation reactions of acyclic, chiral α-amino-β-hydroxy aldehydes containing four contiguous stereocenters were conducted. Allylation mediated by MgBr2∙OEt2 afforded the anti-product. A plausible mechanism of the allylation reaction is also described. The resulting allylation product was used for the total synthesis of (+)-1-epi-castanospermine.
- Published
- 2019
22. Stereoselective Total Syntheses of (+)-Castanospermine and Neu5Ac Methyl Ester
- Author
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Jihun Kang, Yong-Taek Lee, Won-Hun Ham, and In-Soo Myeong
- Subjects
chemistry.chemical_compound ,Castanospermine ,chemistry ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Stereoselectivity ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Abstract
Concise and stereocontrolled total syntheses of (+)-castanospermine and N-acetylneuraminic acid methyl ester were achieved from diastereomerically enriched anti, syn, syn-1,3-oxazine and anti, syn, anti-1,3-oxazine, respectively. The key step in this strategy was the stereoselective BF3·OEt2-mediated allylation.
- Published
- 2019
23. Synthesis and biological activity of diastereoisomeric octahydro-1H-indole-5,6,7-triols, analogues of castanospermine
- Author
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Sergej Šesták, Martina Pilátová, Michael Široký, Miroslava Martinková, Mária Vilková, Samuel Homolya, and Jozef Gonda
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Indole test ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Biological activity ,Shikimic acid ,010402 general chemistry ,Metathesis ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Overman rearrangement ,chemistry.chemical_compound ,chemistry ,Castanospermine ,Drug Discovery ,Stereoselectivity ,Glycoside hydrolase - Abstract
A straightforward stereoselective route towards (3aR,5R,6S,7R,7aR)- and (3aR,5R,6S,7R,7aR)-octahydro-1H-indole-5,6,7-triol, analogues of castanospermine, starting from the corresponding shikimic acid derivatives is described. The key transformations of this approach are the Overman rearrangement and ring-closing metathesis to form the diastereoisomeric cis-fused (5R,6S,7R)-octahydro-1H-indole-5,6,7-triols in good overall yields. Evaluation for in vitro cytotoxicity revealed for some prepared compounds significant antiproliferative activity and weak glycosidase inhibition.
- Published
- 2019
24. Differential effect of combined lipase deficiency (cld/cld) on human hepatic lipase and lipoprotein lipase secretion
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Jennifer C. Boedeker, Mark H. Doolittle, and Ann L. White
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calnexin ,castanospermine ,endoplasmic reticulum ,fetal hepatocytes ,glucosidase enzymes ,Biochemistry ,QD415-436 - Abstract
Combined lipase deficiency (cld) is a recessively inherited disorder in mice associated with a deficiency of LPL and hepatic lipase (HL) activity. LPL is synthesized in cld tissues but is retained in the endoplasmic reticulum (ER), whereas mouse HL (mHL) is secreted but inactive. In this study we investigated the effect of cld on the secretion of human HL (hHL) protein mass and activity. Differentiated liver cell lines were derived from cld mice and their normal heterozygous (het) littermates by transformation of hepatocytes with SV40 large T antigen. After transient transfection with lipase expression constructs, secretion of hLPL activity from cld cells was only 12% of that from het cells. In contrast, the rate of secretion of hHL activity and protein mass per unit of expressed hHL mRNA was identical for the two cell lines. An intermediate effect was observed for mHL, with a 46% reduction in secretion of activity from cld cells. The ER glucosidase inhibitor, castanospermine, decreased secretion of both hLPL and hHL from het cells by ~70%, but by only ~45% from cld cells. This is consistent with data suggesting that cld may result from a reduced concentration of the ER chaperone calnexin. In conclusion, our results demonstrate a differential effect of cld on hLPL, mHL, and hHL secretion, suggesting differential requirements for activation and exit of the enzymes from the ER.—Boedeker, J. C., M. H. Doolittle, and A. L. White. Differential effect of combined lipase deficiency (cld/cld) on human hepatic lipase and lipoprotein lipase secretion.
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- 2001
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25. Isolation and SAR studies of bicyclic iminosugars from Castanospermum australe as glycosidase inhibitors.
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Kato, Atsushi, Hirokami, Yuki, Kinami, Kyoko, Tsuji, Yutaro, Miyawaki, Shota, Adachi, Isao, Hollinshead, Jackie, Nash, Robert J., Kiappes, J.L., Zitzmann, Nicole, Cha, Jin K., Molyneux, Russell J., Fleet, George W.J., and Asano, Naoki
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IMINOSUGARS , *CASTANOSPERMINE , *GLYCOSIDASE inhibitors , *PYRROLIZIDINES , *MANNOSIDASES , *COMPARATIVE studies - Abstract
We report the isolation and structural determination of fourteen iminosugars, containing five pyrrolizidines and five indolizidines, from Castanospermum australe . The structure of a new alkaloid was elucidated by spectroscopic methods as 6,8-di epi -castanospermine ( 13 ). Our side-by-side comparison between bicyclic and corresponding monocyclic iminosugars revealed that inhibition potency and spectrum against each enzyme are clearly changed by their core structures. Castanospermine ( 10 ) and 1-deoxynojirimycin (DNJ) have a common d - gluco configuration, and they showed the expected similar inhibition potency and spectrum. In sharp contrast, 6- epi -castanospermine ( 12 ) and 1-deoxymannojirimycin ( manno -DNJ) both have the d - manno configuration but the α-mannosidase inhibition of 6- epi -castanospermine ( 12 ) was much better than that of manno -DNJ. 6,8-Di epi -castanospermine ( 13 ) could be regarded as a bicyclic derivative of talo -DNJ, but it showed a complete loss of α-galactosidase A inhibition. This behavior against α-galactosidase A is similar to that observed for 1- epi -australine ( 6 ) and altro -DMDP. [ABSTRACT FROM AUTHOR]
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- 2015
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26. Synthesis of Multibranched Australine Derivatives from Reducing Castanospermine Analogues through the Amadori Rearrangement of gem-Diamine Intermediates: Selective Inhibitors of β-Glucosidase.
- Author
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Sánchez-Fernández, Elena M., Álvarez, Eleuterio, Mellet, Carmen Ortiz, and García Fernández, José M.
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- *
PYRROLIZIDINES , *IMINOSUGARS , *CASTANOSPERMINE , *CHEMICAL synthesis , *ANOMERIC effect , *DIASTEREOISOMERS - Abstract
A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp²-iminosugar-type reducing castanospermine precursor is reported. The transformation involves a gem-diamine intermediate that undergoes the indolizidine → pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of β-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. Natural Products Database Screening for the Discovery of Naturally Occurring SARS‐Cov‐2 Spike Glycoprotein Blockers
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Mahmoud E. S. Soliman, Mehboobali Pannipara, Bijo Mathew, Sanal Dev, Simone Carradori, Abdullah G. Al-Sehemi, and Fisayo A. Olotu
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chemistry.chemical_classification ,Castanospermine ,Virtual screening ,Natural product ,library screening ,In silico ,Communication ,coronavirus ,COVID-19 ,Computational biology ,General Chemistry ,Biology ,medicine.disease_cause ,Virus ,Communications ,chemistry.chemical_compound ,chemistry ,Docking (molecular) ,karuquinone B ,medicine ,Medicinal Chemistry & Drug Discovery ,Glycoprotein ,spike glycoprotein ,Coronavirus - Abstract
SARS‐CoV‐2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best‐in‐class derivatives in silico able to target an essential structure of the virus and to act in the early stage of infection., We identified from a database, specialized in natural products, Karuquinone B and Castanospermine as blockers of SARS‐CoV‐2 spike glycoprotein in silico. First, we validated a docking protocol able to refine the most suitable compounds. Then, we studied by molecular dynamics the interactions between the two compounds and the biological target. The two compounds were also characterized in terms of botanical and chemical characteristics, and pharmacokinetic parameters in silico.
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- 2020
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28. Carboxybenzyl Group as an O-Nucleophilein the C–H Allylic Oxidation: Total Synthesis of (−)-Castanospermine.
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Malik, Michał, Witkowski, Grzegorz, and Jarosz, Sławomir
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- *
CARBOXYL group , *NUCLEOPHILES , *CARBON-hydrogen bonds , *OXIDATION , *CASTANOSPERMINE , *CHEMICAL synthesis , *RARE earth metals - Abstract
Thefirst palladium-mediated C–H allylic oxidation witha Cbz group acting as an O-nucleophile is reported.It was found that this transformation is promoted by rare-earth metaltriflates: Yb(OTf)3or Sc(OTf)3. A possiblecatalytic cycle is proposed. This reaction was applied in the synthesisof a d-xylose derived oxazolidinon, a versatile intermediateused further in the stereoselective synthesis of unnatural (−)-castanospermine.Cyclization of the key intermediate with PhSeBr afforded the desiredbicyclic scaffold. In an alternative route, hydroboration/oxidationfollowed by DPPA-mediated cyclization was used. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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29. Efficient asymmetric syntheses of alkaloids and medicinally relevant molecules based on heterocyclic chiral building blocks.
- Author
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Wang, Ai-E and Huang, Pei-Qiang
- Subjects
- *
ASYMMETRIC synthesis , *BLOCKS (Building materials) , *ALKALOIDS , *HETEROCYCLIC chemistry , *AMIDES , *CASTANOSPERMINE - Abstract
In this report, we present recent progress in synthetic methodologies based on three heterocyclic chiral building blocks developed from our laboratories. The potential of these chiral building block-based methods in the concise asymmetric synthesis of alkaloids and medicinally interesting molecules has been demonstrated by the total syntheses of 8-aza-prostaglandin E1, 11-hydroxylated analogues of the lead compounds CP-734432 and PF-04475270, (+)-castanospermine, (+)-1- epi-castanospermine, 7-deoxy-6- epi-castanospermine as well as 9- epi-sessilifoliamide J. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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30. Structure and Activity of the Streptomyces coelicolor A3(2) β-N-Acetylhexosaminidase Provides Further Insight into GH20 Family Catalysis and Inhibition.
- Author
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Nhung Nguyen Thi, Offen, Wendy A., Shareck, François, Davies, Gideon J., and Doucet, Nicolas
- Subjects
- *
STREPTOMYCES coelicolor , *GLYCOSIDASES , *HEXOSAMINIDASE , *HYDROLYSIS , *CASTANOSPERMINE - Abstract
β-N-acetylhexosaminidases (HEX) are glycosidases mat catalyze the glycosidic linkage hydrolysis of gluco- and galacto-configured N-acetyl-β-D-hexosaminides. These enzymes are important in human physiology and are candidates for the biocatalytic production of carbohydrates and glycomimetics. In this study, the three-dimensional structure of the wild-type and catalytically impaired E302Q HEX variant from the soil bacterium Streptomyces coelicolor A3(2) ( ScHEX) were solved in ligand-free forms and in the presence of 6-acetamido-6-deoxy-castanospermine (6-Ac-Cas). The E302Q variant was also trapped as an intermediate with oxazoline bound to the active center. Crystallographic evidence highlights structural variations in the loop 3 environment, suggesting conformational heterogeneity for important active-site residues of this GH20 family member. The enzyme was investigated for its β-N-acetylhexosaminidase activity toward chitooligomers and pNP-acetyl gluco- and galacto-configured N-acetyl hexosaminides. Kinetic analyses confirm the β(1-4) glycosidic linkage substrate preference, and HPLC profiles support an exoglycosidase mechanism, where the enzyme cleaves sugars from the nonreducing end of substrates. ScHEX possesses significant activity toward chitooligosaccharides of varying degrees of polymerization, and the final hydrolytic reaction yielded pure GlcNAc without any byproduct, promising high applicability for the enzymatic production of this highly valued chemical. Thermostability and activation assays further suggest efficient conditions applicable to the enzymatic production of GlcNAc from chitooligomers. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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31. Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: total synthesis of (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity.
- Author
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Singh, Priyanka, Manna, Sudipta Kumar, and Panda, Gautam
- Subjects
- *
HYDROXYLATION , *INDOLIZIDINES synthesis , *PIPERIDINE , *CASTANOSPERMINE , *ALDEHYDES , *INDOLIZIDINES , *SWAINSONINE - Abstract
Abstract: Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation. [Copyright &y& Elsevier]
- Published
- 2014
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32. Analgesic, Anti-Inflammatory, and GC-MS Studies on Castanospermum australe A. Cunn. & C. Fraser ex Hook.
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Sajeesh, Thankarajan and Parimelazhagan, Thangaraj
- Subjects
ANALGESICS ,GAS chromatography/Mass spectrometry (GC-MS) ,CASTANOSPERMINE ,PHYTOCHEMICALS ,SOLVENT extraction - Abstract
The present study was aimed to evaluate the analgesic and anti-inflammatory properties of Castanospermum australe and to profile phytochemicals by GC-MS. The ethanolic extracts were prepared by successive solvent extraction using Soxhlet apparatus. The analgesic activity was analyzed by hot plate method and acetic acid-induced writhing test whereas anti-inflammatory study was done by carrageenan induced paw oedema model. The acute toxicity study revealed that ethanol extracts of leaf and bark of C. australe were safe even at a higher dose of 2000 mg/kg whereas ethanol extract of seed was toxic at the same dose. In both hot plate method (5.85 s) and acetic acid-induced writhing test (57%), the leaf ethanol extract exhibited significant analgesic activity (P < 0.001) at a dose of 400 mg/kg. The anti-inflammatory activity of leaf extract was exhibited by the reduction in paw linear diameter by 64.76% at 400 mg/kg in carrageenan induced paw oedema. The GC-MS analysis of the ethanol extract of leaf revealed sixteen major compounds of which 1,7-dimethyl-4,10-dioxa-1,7-diazacyclododecane, (+)-N-methylephedrine, and permethylspermine were found to be pharmaceutically and the most important. These findings justify that C. australe can be a valuable natural analgesic and anti-inflammatory source which seemed to provide potential phytotherapeutics against various ailments. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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33. Castanospermine reduces Zika virus infection-associated seizure by inhibiting both the viral load and inflammation in mouse models
- Author
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Yichen Cheng, Hengli Tang, Anil Mathew Tharappel, Eric H. Holmes, and Gary K. Ostrander
- Subjects
0301 basic medicine ,Drug ,Male ,Castanospermine ,Microcephaly ,media_common.quotation_subject ,030106 microbiology ,Inflammation ,Antiviral Agents ,Zika virus ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Seizures ,Virology ,Cell Line, Tumor ,Chlorocebus aethiops ,Paralysis ,medicine ,Animals ,Humans ,Vero Cells ,media_common ,Pharmacology ,biology ,business.industry ,Zika Virus Infection ,Indolizines ,Outbreak ,Viral Load ,biology.organism_classification ,medicine.disease ,Seizure ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,Female ,medicine.symptom ,business ,Glioblastoma ,Viral load ,Immunosuppressive Agents ,Research Paper - Abstract
Zika virus (ZIKV) outbreaks have been reported worldwide, including a recent occurrence in Brazil where it spread rapidly, and an association with increased cases of microcephaly was observed in addition to neurological issues such as GBS that were reported during previous outbreaks. Following infection of neuronal tissues, ZIKV can cause inflammation, which may lead to neuronal abnormalities, including seizures and paralysis. Therefore, a drug containing both anti-viral and immunosuppressive properties would be of great importance in combating ZIKV related neurological abnormalities. Castanospermine (CST) is potentially a right candidate drug as it reduced viral load and brain inflammation with the resulting appearance of delayed neuronal disorders, including seizures and paralysis in an Ifnar1-/- mouse., Highlights • Anti-ZIKV activity of castanospermine (CST) In vivo and in vitro. • CST reduces ZIKV induced inflammation of brain. • CST delays the ZIKV induced seizure and improves neuronal disorders such as motor function. • CST gives marginal improvement in survivability in Ifnar1-/- mice.
- Published
- 2020
34. Epitope Shaving Promotes Fungal Immune Evasion
- Author
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Neil A. R. Gow, Delma S. Childers, Judith M. Bain, Daniel E. Larcombe, Gabriela Mol Avelar, Arnab Pradhan, Alistair J. P. Brown, Mihai G. Netea, and Lars P. Erwig
- Subjects
Male ,Phagocytosis ,Cell ,Xog1 exoglucanase ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Virulence ,Moths ,Microbiology ,Epitope ,Host-Microbe Biology ,Epitopes ,Mice ,Immune system ,Virology ,Candida albicans ,medicine ,Extracellular ,Cellulose 1,4-beta-Cellobiosidase ,Animals ,Anaerobiosis ,Lactic Acid ,immune evasion ,biology ,Macrophages ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Corpus albicans ,QR1-502 ,virulence ,Mice, Inbred C57BL ,medicine.anatomical_structure ,castanospermine ,Larva ,cell wall ,β-glucan shaving ,Metabolic Networks and Pathways ,Research Article - Abstract
The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion., The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes.
- Published
- 2020
35. A simple and portable method for β-Glucosidase activity assay and its inhibitor screening based on a personal glucose meter
- Author
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Guo-Ying Chen, Hao Zhang, and Feng-Qing Yang
- Subjects
Detection limit ,Chromatography ,biology ,Glucose meter ,Blood Glucose Self-Monitoring ,Hydrolysis ,beta-Glucosidase ,Biochemistry ,Enzyme assay ,Analytical Chemistry ,Molecular Docking Simulation ,chemistry.chemical_compound ,Glucose ,chemistry ,Castanospermine ,biology.protein ,Vanillic acid ,Environmental Chemistry ,Gallic acid ,Ferricyanide ,Spectroscopy - Abstract
In this study, a simple and portable enzyme activity assay and inhibitor screening method was developed based on β-Glucosidase-mediated cascade reaction in a personal glucose meter (PGM). The inhibition of castanospermine (β-Glucosidase inhibitor) on β-Glucosidase leads to reducing the yields of glucose and saligenin produced by the catalysis hydrolysis of D (−)-Salicin. The ferricyanide (K3 [Fe(CN)6]) can be reduced by the products of glucose and saligenin to form ferrocyanide ([K4[Fe(CN)6]) in the glucose strips, and thereby get the electron to generate PGM detectable signals. This strategy can realize the direct determination of glucose and saligenin using PGM as simple as measuring the glucose in blood. Under the optimum experimental conditions, quantitative detection of β-Glucosidase in crude almond sample was achieved within the ranges of 1.0–9.0 U/mL with the limit of detection of 0.45 U/mL. The recoveries of β-Glucosidase spiked with two different concentrations (3.0 and 6.0 U/mL) in the crude bitter almond extracts were determined as 96.2% and 84.3%, respectively. Furthermore, gallic acid, protocatechualdehyde, cryptochlorogenic acid, epigallocatechin, epicatechin and vanillic acid exhibited good inhibitory effect (all higher than 40%) on β-Glucosidase. In addition, tea polyphenol extracts of raw Pu-erh and Fuding white tea had good inhibition potency and the % of inhibition were (29.0 ± 3.5)% and (21.1 ± 2.2)% on β-Glucosidase, respectively. Finally, molecular docking study indicated that hydrogen bonding plays an important role in the interaction between the compounds and β-Glucosidase. The enzyme activity assay and inhibitor screening method developed in present study using PGM based on β-Glucosidase-mediated cascade reaction would be of value for expanding the application of PGM in non-glucose target analysis.
- Published
- 2020
36. Iminosugars With Endoplasmic Reticulum α-Glucosidase Inhibitor Activity Inhibit ZIKV Replication and Reverse Cytopathogenicity in vitro
- Author
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Suresh V. Kuchipudi, Levina Lim, Shubhada K. Chothe, Gitanjali Bhushan, Ian M. Bird, and Ruth H. Nissly
- Subjects
Microbiology (medical) ,Programmed cell death ,iminosugar ,lcsh:QR1-502 ,Biology ,Microbiology ,lcsh:Microbiology ,Virus ,Zika virus ,Celgosivir ,03 medical and health sciences ,chemistry.chemical_compound ,celgosivir ,Cytotoxicity ,Original Research ,030304 developmental biology ,0303 health sciences ,ER-AGI ,030306 microbiology ,Endoplasmic reticulum ,antiviral ,Virology ,In vitro ,castanospermine ,DNJ ,Castanospermine ,chemistry ,Apoptosis - Abstract
Zika virus (ZIKV), a vector-borne virus of the family Flaviviridae, continues to spread and remains a significant global public health threat. Currently, there are no approved vaccines or antivirals against ZIKV. We investigated the anti-ZIKV ability of three iminosugars with endoplasmic reticulum α-glucosidase inhibitor (ER-AGI) activity, namely deoxynojirimycin (DNJ), castanospermine, and celgosivir. None of the three iminosugars showed any significant cytotoxicity in Vero or human microglia CHME-3 cells when applied for 72 h at concentrations up to 100 μM. Iminosugar treatment of Vero or CHME-3 cells prior to ZIKV infection resulted in significant inhibition of ZIKV replication over 48 hours. Reduction in ZIKV replication in iminosugar-treated cells was not associated with any significant change in the expression levels of key antiviral genes. Following infection with three different strains of ZIKV, iminosugar-treated Vero or CHME-3 cells showed no cell death, whereas vehicle-treated control cells exhibited 50-60% cell death at 72 h post-infection (hpi). While there was no significant difference in apoptosis between iminosugar-treated and control cells, iminosugar-treated cells exhibited a substantial reduction of necrosis at 72 hpi following ZIKV infection. In summary, iminosugars with ER-AGI activity inhibit ZIKV replication and significantly reduce necrosis without altering the antiviral gene expression and apoptosis of infected human cells. The results of this study strongly suggest that iminosugars are promising anti-ZIKV antiviral agents and such warrant further in vivo studies.
- Published
- 2020
37. Bioactive Indolizidine Alkaloids
- Author
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P. R. Dorling and S. M. Colegate
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,Swainsonine ,Indolizidines ,Castanospermine ,chemistry ,Biochemistry ,Glycomimetic ,Indolizine ,Indolizidine ,Oligosaccharide ,Glycoprotein - Abstract
Complete hydrogen saturation of the indolizine system produces the indolizidine (octahydroindolizine) heterocyclic ring system. Swainsonine, the first water-soluble, polyhydroxylated indolizidine to be reported, was first isolated from, and named after, the toxic Australian legume Swainsona canescens. The potential medical uses of swainsonine have been extensively studied and well reviewed. Briefly, however, swainsonine has potential as a modulator of the immune system as a consequence of its ability to stimulate interleukin 2 production by T-helper cells, and consequent proliferation of T-lymphocytes. It is also effective as an anti-metastasis agent, inhibiting the spread of some tumors, possibly due to its activity in altering oligosaccharide processing by inhibiting complex glycosidation of glycoproteins. As with the glycomimetic swainsonine and related alkaloids, the biological activities of castanospermine and related indolizidines also involve the inhibition of glycosidases.
- Published
- 2020
38. A 'turn off-on' fluorescent nanoprobe consisting of CuInS2 quantum dots for determination of the activity of β-glucosidase and for inhibitor screening
- Author
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Ziping Liu, Edith Bai, Yang Han, Shasha Liu, Yanan Li, Zhiwei Xu, and Ye Tian
- Subjects
Detection limit ,Cyanide ,010401 analytical chemistry ,Nanoprobe ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,Fluorescence ,0104 chemical sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Castanospermine ,chemistry ,Thiourea ,Quantum dot ,Enzymatic hydrolysis ,0210 nano-technology ,Nuclear chemistry - Abstract
A fluorescent “turn off-on” nanoprobe is described for highly sensitive and selective determination of the activity of the enzyme β-glucosidase (β-Glu). Firstly, cysteine modified CuInS2 quantum dots (Cys-CuInS2 QDs) were prepared from indium(III) and copper(II) salts and the presence of thiourea. The red fluorescence of the Cys-CuInS2 QDs, with excitation/emission maxima at 590/656 nm, is quenched by Cu(II). However, in the presence of β-Glu and the cyanogenic glycoside, enzymatic hydrolysis leads to the formation of cyanide. The latter competitively binds to Cu(II) owing to its high affinity for cyanide. This restores the fluorescence of the Cys-CuInS2 QDs. Under the optimum conditions, fluorescence increases linearly in the 0.5–700 U·L−1 β-Glu activity range. The detection limit is 0.2 U·L−1. The nanoprobe was applied to analyze spiked soil samples, and satisfactory results were obtained. The average recoveries of β-Glu were in the range of 96–103%, and the RSD was lower than 4.0%. The fluorescent probe can also be used to screen for β-Glu inhibitors as demonstrated for castanospermine as an example.
- Published
- 2019
39. Direct and highly stereoselective synthesis of quinolizidine iminosugars promoted by <scp>l</scp>-proline-Et3N
- Author
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Peng Liang, Wen Yuan, Xiaoke Zhang, Huawu Shao, Jichao Zhang, Wei Jiao, and Yang Pan
- Subjects
chemistry.chemical_classification ,Quinolizidine ,010405 organic chemistry ,Stereochemistry ,education ,Organic Chemistry ,Enantioselective synthesis ,Iminosugar ,Indolizidine ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Aldehyde ,humanities ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Castanospermine ,1,3-Dipolar cycloaddition ,Stereoselectivity ,Physical and Theoretical Chemistry - Abstract
A mild and effective method for the synthesis of polyhydroxylated quinolizidine iminosugars is described. The Mannich-type reaction of iminosugar C-glycosides with aldehyde in the presence of L-proline-Et3N provides polyhydroxylated quinolizidine iminosugars, and desired products as the potential glucosidase inhibitors were obtained in good to excellent yields with excellent stereoselectivity.
- Published
- 2018
40. New Castanospermine Glycoside Analogues Inhibit Breast Cancer Cell Proliferation and Induce Apoptosis without Affecting Normal Cells.
- Author
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Allan, Ghada, Ouadid-Ahidouch, Halima, Sanchez-Fernandez, Elena M., Risquez-Cuadro, Rocío, Fernandez, José M. Garcia, Ortiz-Mellet, Carmen, and Ahidouch, Ahmed
- Subjects
- *
CASTANOSPERMINE , *GLYCOSIDES , *BREAST cancer , *CANCER cell proliferation , *APOPTOSIS , *IMINOSUGARS , *ANTINEOPLASTIC agents - Abstract
sp2-Iminosugar-type castanospermine analogues have been shown to exhibit anti-tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231 breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of CDK4 (cyclin-dependent kinase 4), cyclin D1 and cyclin E expression, pRb phosphorylation, and an overexpression of p21Waf1/Cip1. In MDA-MB-231 cells, CO-OCS reduced CDK1 but not cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression, cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these castanospermine analogues may constitute potential anti-cancer agents against breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
41. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial
- Author
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Watanabe, Satoru, Rathore, Abhay P.S., Sung, Cynthia, Lu, Fan, Khoo, Yok Moi, Connolly, John, Low, Jenny, Ooi, Eng Eong, Lee, How Sung, and Vasudevan, Subhash G.
- Subjects
- *
CASTANOSPERMINE , *DRUG efficacy , *DENGUE viruses , *VIRAL disease prevention , *DOSE-effect relationship in pharmacology , *CLINICAL trials , *GLUCOSIDASES , *SEROTYPES , *LABORATORY mice - Abstract
Abstract: Celgosivir (6-O-butanoyl castanospermine), a pro-drug of the naturally occurring castanospermine, is an inhibitor of α-glucosidase I and II that is found to be a potent inhibitor of several enveloped viruses including all four serotypes of dengue virus. We showed previously that the compound fully protected AG129 mice from lethal infection with a mouse adapted dengue virus at a dose of 50mg/kg twice daily (BID) for 5days and was effective even after 48h delayed treatment. Here we show that the protection by celgosivir is dose- and schedule-dependent and that a twice-a-day regimen of 50, 25 or 10mg/kg is more protective than a single daily dose of 100mg/kg. Treatment with 50mg/kg BID castanospermine had comparable efficacy as 25mg/kg BID celgosivir, suggesting that celgosivir is approximately twice as potent as castanospermine with respect to in vivo antiviral efficacy. Pharmacokinetics (PK) studies of celgosivir in mice showed that it rapidly metabolized to castanospermine. Simulation of the PK data with the survival data for the various doses of celgosivir tested suggests that the steady-state minimum concentration is a critical parameter to note in choosing dose and schedule. These results influenced the selection of the dose regimen for a proof-of-concept clinical trial of celgosivir as a treatment against dengue fever. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
42. The effects of Castanospermine, an oligosaccharide processing inhibitor, on mononuclear/endothelial cell binding and the expression of cell adhesion molecules.
- Author
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Hibberd, Adrian D., Trevillian, Paul R., Clark, David A., Mcelduff, Patrick, and Cowden, William B.
- Subjects
- *
CASTANOSPERMINE , *OLIGOSACCHARIDES , *ENDOTHELIAL cells , *CELL adhesion molecules , *GENE expression , *IMMUNOSUPPRESSIVE agents , *MONOCYTES - Abstract
Introduction: In this study we aimed to determine whether Castanospermine, a transplant immunosuppressive agent, impaired mononuclear/endothelial cell binding and expression of their cell adhesion molecules. Methods: The binding of human umbilical vein endothelial cells with peripheral blood mononuclear cells was measured by a binding assay using Chromium 51 label; the membrane expression of cell adhesion molecules was measured by flow cytometry expressed as mean fluorescence intensity ratios. Results: Castanospermine decreased mononuclear/endothelial cell binding if and only if both cell types were treated with Castanospermine: this impairment occurred if endothelial cells were treated with a range of doses of Castanospermine and mononuclear cells were treated with a constant dose of Castanospermine (p<0.001 versus untreated p=0.978) or vice versa (p = 0.004 versus untreated p = 0.582). Upon human umbilical vein endothelial cells Castanospermine reduced the mean fluorescence intensity ratios of Eselectin (p=0.003), ICAM-1 (p<0.001), ICAM-2 (p=0.004) and PECAM-1 (p<0.001) but increased it for P-selectin (p<0.001). Upon peripheral blood mononuclear cells Castanospermine reduced the mean fluorescence intensity ratios of L-selectin (P<0.001), LFA-1α (p<0.001), VLA-4 (p<0.001), Mac-1 (P<0.001) and CR4 (p<0.001) but increased the mean fluorescence intensity ratios of PSGL-1 (p<0.001) and PECAM-1 (p = 0.001 ). Similar changes in mean fluorescence intensity ratios were found in the subset of lymphocytes and monocytes but the reductions in LFA-1α and VLA-4 on lymphocytes and Mac-1 and CR4 on monocytes were greater. Conclusions: The reduction in mononuclear/endothelial cell binding mediated by CAST and the reduction in expression of multiple cell adhesion molecules on these cell types help to explain the mechanism of its established immunosuppressive effect. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
43. Computer analysis of metagenomic data-Pediction of quantitative value of specific activity of proteins.
- Author
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Ivanisenko, V., Demenkov, P., Pintus, S., Ivanisenko, T., Podkolodny, N., Ivanisenko, L., Rozanov, A., Bryanskaya, A., Kostrjukova, E., Levizkiy, S., Selezneva, O., Chukin, M., Larin, A., Kondratov, I., Lazarev, V., Peltek, S., Govorun, V., and Kolchanov, N.
- Subjects
- *
MICROBIOLOGY , *COMPUTER systems , *CASTANOSPERMINE , *PROTEIN structure , *COMPUTERS in microbiology - Abstract
The article presents a study which proposes a high-performance computer system designed for pipeline processing of metagenomic data. It states that microbial communities of bottomset beds of Lake Krotov'ya Lyaga in Novosibirsk region in Russia were analyzed using the Protein Structure Discovery (PSD) computer-based system. The result found that the spatial structure of the potential protein binding site contains a binding site for castanospermine.
- Published
- 2012
- Full Text
- View/download PDF
44. Synthesis of 8-epi-castanospermine and 6,7,8-tri-epi-castanospermine
- Author
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St-Denis, Yves and Chan, Tak Hang
- Subjects
Castanospermine ,Amino acids ,Hydrogen ,Enzymes ,Optical isomers ,Enantiomers ,Chemical research -- Analysis - Abstract
8-epi-Castanospermine (11) and 6,7,8-tri-epi-castanospermine (12) were synthesized from the hydroxyproline precursor 13 which was obtained enantioselectively via an enzymatic process. Key words: castanospermine, synthesis of, enzymatic reduction, enzymatic resolution, asymmetric synthesis.
- Published
- 2000
45. A concise stereoselective synthesis of (+)-1-deoxy-6-epi-castanospermine.
- Author
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Gajare, Vikas S., Khobare, Sandip R., Datrika, Rajender, Reddy, K. Srinivasa, Rajana, Nagaraju, Babu, B. Kishore, Rao, B. Venkateswara, and Syam Kumar, U.K.
- Subjects
- *
STEREOSELECTIVE reactions , *CASTANOSPERMINE , *ANTI-inflammatory agents , *CHEMICAL synthesis , *INDOLIZIDINES , *HYDROXYLATION - Abstract
A concise stereoselective synthesis of (+)-1-deoxy-6- epi -castanospermine has been developed through stereoselective approach from the chiral precursor R -Glycidol. The key steps in the synthesis involve Grignard reaction through Weinreb amide, followed by Sharpless dihydroxylation and stereoselective reduction of imine assigned the required stereochemical feature of indolizidine azasugar (+)-1-deoxy-6- epi -castanospermine. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. The Comparative Pathology of the Glycosidase Inhibitors Swainsonine, Castanospermine, and Calystegines A3, B2, and C1 in Mice.
- Author
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STEGELMEIER, BRYAN L., MOLYNEUX, RUSSELL J., ASANO, NAOKI, WATSON, ALISON A., and NASH, ROBERT J.
- Subjects
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SWAINSONINE , *ANKLEBONE , *IPOMOEA , *ASTRAGALUS (Plants) , *GLYCOSIDASES , *BIOCHEMISTRY - Abstract
To study various polyhydroxy-alkaloid glycosidase inhibitors, 16 groups of 3 mice were dosed using osmotic minipumps with swainsonine (0, 0.1, 1, and 10 mg/kg/day), castanospermine, and calystegines A3, B2, and C1 (1, 10, and 100 mg/kg/day). After 28 days, the mice were euthanized, necropsied, and examined using light and electron microscopy. The high-dose swainsonine-treated mice developed neurologic disease with neuro-visceral vacuolation typical of locoweed poisoning. Castanospermine- and calystegines-treated mice were clinically normal; however, high-dose castanospermine--treated mice had thyroid, renal, hepatic, and skeletal myocyte vacuolation. Histochemically, swainsonine- and castanospermine-induced vacuoles contained mannose-rich oligosaccharides. High-dose calystegine A3--treated mice had increased numbers of granulated cells in the hepatic sinusoids. Electron microscopy, lectin histochemistry, and immunohistochemistry suggest these are pit cells (specialized NK cells). Histochemically, the granules contain glycoproteins or oligosaccharides with abundant terminal N-acetylglucosamine residues. Other calysteginetreated mice were histologically normal. These findings indicate that swainsonine produced lesions similar to locoweed, castanospermine caused vacuolar changes with minor changes in glycogen metabolism, and only calystegine A3 produced minimal hepatic changes. These also suggest that in mice calystegines and castanospermine are less toxic than swainsonine, and as rodents are relatively resistant to disease, they are poor models to study such induced storage diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
47. A concise approach to (+)-1-epi-castanospermine
- Author
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Wu, Tian-Jun and Huang, Pei-Qiang
- Subjects
- *
ENANTIOSELECTIVE catalysis , *HETEROGENEOUS catalysis , *ACIDS , *CHEMISTRY - Abstract
Abstract: A concise enantioselective synthesis of (+)-1-epi-castanospermine (2) is described, which featured the use of chiral non-racemic tetramic acid derivative 5 as a synthetic equivalent of the challenging synthon A through a highly diastereoselective vinylogous Mukaiyama type reaction. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
48. Synthesis and evaluation of 1-deoxy-8-epi-castanospermine, 1-deoxy-8-hydroxymethyl castanospermine, and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol
- Author
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Pandey, Ganesh, Dumbre, Shrinivas G., Pal, Sujit, Khan, M. Islam, and Shabab, M.
- Subjects
- *
DIASTEREOISOMERS , *OPTICAL isomers , *CHEMICAL bonds , *GLUCOSIDASES - Abstract
Abstract: A short, versatile, and enantioselective synthesis of 1-deoxy-8-epi-castanospermine (5), 1-deoxy-8-hydroxymethyl castanospermine (6), and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol (7) is achieved from a common template 12. The key step utilized is PET provoked amine radical cyclization of 11 to 12 in excellent diastereoselectivity. The exocyclic double bond at C-8 of the template is functionalized to obtain 5–7 as exclusive diastereomers. 1-Deoxy-8-epi-castanospermine exhibited inhibition of α- and β-galactosidase and β-glucosidase. Compounds 6 and 7 were found to be weak inhibitors of β-glucosidase. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
49. 4,5-erythro/5,6-threo-Stereoselectivity in vinylogous Mukaiyama aldol addition of a silyloxypyrrole to a threose derivative: stereochemical rationalization and relevance to (+)-castanospermine synthesis
- Author
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Hunter, Roger, Rees-Jones, Sophie C.M., and Su, Hong
- Subjects
- *
CONDENSATION products (Chemistry) , *ALDOL condensation , *STEREOCHEMISTRY , *ORGANIC chemistry - Abstract
Abstract: Vinylogous Mukaiyama aldol addition of N-p-methoxybenzyl-4-methoxy-2-trimethylsilyloxypyrrole 7 to bis-MOM threose 6 using SnCl4 as promoter gave the 4,5-erythro/5,6-threo adduct 8, with the correct absolute configurations for the castanospermine framework as determined by a single-crystal X-ray structure. A transition-state model is presented to rationalize the stereoselectivity. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
50. Monitoring chaperone engagement of substrates in the endoplasmic reticulum of live cells.
- Author
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Snapp, Erik L., Sharma, Ajay, Lippincott-Schwartz, Jennifer, and Hegde, Ramanujan S.
- Subjects
- *
ENDOPLASMIC reticulum , *FLUORESCENCE , *LECTINS , *CALRETICULIN , *PUROMYCIN , *HOMEOSTASIS - Abstract
The folding environment in the endoplasmic reticulum (ER) depends on multiple abundant chaperones that function together to accommodate a range of substrates. The ways in which substrate engagement shapes either specific chaperone dynamics or general ER attributes in vivo remain unknown. In this study, we have evaluated how changes in substrate flux through the ER influence the diffusion of both the lectin chaperone calreticulin and an inert reporter of ER crowdedness. During acute changes in substrate load, the inert probe revealed no changes in ER organization, despite significant changes in calreticulin dynamics. By contrast, inhibition of the lectin chaperone system caused rapid changes in the ER environment that could be reversed over time by easing new substrate burden. Our findings provide insight into the normal organization and dynamics of an ER chaperone and characterize the capacity of the ER to maintain homeostasis during acute changes in chaperone activity and availability. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
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