Synthesis and glycosidase inhibitory activity of noeurostegine—a new and potent inhibitor of β-glucoside hydrolases

2010 ◽  
Vol 8 (2) ◽  
pp. 433-441 ◽  
Author(s):  
Tina Secher Rasmussen ◽  
Henrik Helligsø Jensen
Keyword(s):  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
Glucoside Hydrolases

scholarly journals Acetylcholinesterase and Butyrylcholinesterase Inhibitory Compounds from Corydalis Cava (Fumariaceae)

2011 ◽  
Vol 6 (5) ◽  
pp. 1934578X1100600 ◽  
Author(s):  
Jakub Chlebek ◽  
Kateřina Macáková ◽  
Lucie Cahlíková ◽  
Milan Kurfürst ◽  
Jiří Kuneš ◽  
...  
Keyword(s):  
Human Blood ◽  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
The Other ◽  
Spectroscopic Techniques ◽  
Dependent Manner ◽  
Isoquinoline Alkaloids ◽  
Chemical Structures ◽  
Inhibitory Compounds ◽  
Dose Dependent

Tubers of Corydalis cava were extracted with ethanol and fractionated using n-hexane, chloroform and ethanol. Repeated column chromatography, preparative TLC and crystallization led to the isolation of fifteen isoquinoline alkaloids. The chemical structures of the isolated compounds were determined on the basis of spectroscopic techniques and by comparison with literature data. All isolated compounds were tested for human blood acetylcholinesterase (HuAChE) and human plasma butyrylcholinesterase (HuBuChE) inhibitory activity. (+)-Canadaline inhibited acetylcholinesterase as well as butyrylcholinesterase in a dose-dependent manner with IC50 values of 20.1 ± 1.1 μM and 85.2 ± 3.2 μM, respectively. (+)-Canadine, with an IC50 value of 12.4 ± 0.9 μM, was the most potent inhibitor of acetylcholinesterase, whilst (±)-corycavidine and (+)-bulbocapnine were effective inhibitors of butyrylcholinesterase with IC50 values of 46.2 ± 2.4 uM and 67.0 ± 2.1 μM, respectively. The other isolated alkaloids were considered inactive (IC50 > 100 μM).

scholarly journals Phosphodiesterase Inhibitory Activity of the Flavonoids and Xanthones from Anaxagorea luzonensis

2015 ◽  
Vol 10 (2) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Chalisa Sabphon ◽  
Prapapan Temkitthawon ◽  
Kornkanok Ingkaninan ◽  
Pattara Sawasdee
Keyword(s):  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
First Report ◽  
Phosphodiesterase Type

Five flavonoids, one isoflavone and five xanthones were isolated from Anaxagorea luzonensis. Of these eleven isolated compounds, 1,3,5-trihydroxy-4-prenylxanthone (3) was a relatively potent inhibitor of phosphodiesterase type 5 (PDE5), with an IC50 value of 3.0 μM. This is the first report showing that natural xanthones can exhibit promising PDE5 inhibitory activity. Moreover, this study revealed that the presence of the C-4 prenyl residue attached to the xanthone core is correlated with the significant PDE5 inhibitory activity.

TFPI-Beta Is An Effective Inhibitor of TF-FVIIa Mediated Coagulation and Tumor Cell Invasion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 347-347
Author(s):  
Susan A Maroney ◽  
Josephine P Ferrel ◽  
Alan E. Mast
Keyword(s):  
Cell Surface ◽  
Inhibitory Activity ◽  
Cho Cells ◽  
Potent Inhibitor ◽  
Terminal Region ◽  
Solution Phase ◽  
Effective Inhibitor ◽  
Wild Type

Abstract Abstract 347 Tissue Factor Pathway Inhibitor (TFPI) is the primary physiological inhibitor of TF-fVIIa, the in vivo activator of blood coagulation. TFPI is an alternatively spliced protein with two major isoforms, TFPI-alpha and TFPI-beta. These isoforms differ in their C-terminal domain structure and their mechanism for cell surface attachment with TFPI-alpha indirectly associating with the endothelial surface through binding to a GPI-floated protein while TFPI-beta is directly attached to a GPI-float. In addition, the isoforms are differentially expressed in mouse tissues, with TFPI-alpha present in placenta, embryo and platelets, while TFPI-beta is the predominant isoform in adult vascular beds. However, TFPI-beta has ∼20-fold decreased activity when compared to TFPI-alpha in solution phase plasma clotting assays. We hypothesized that TFPI-beta will have more physiologically relevant activity when associated with a cell surface instead of in solution phase. To test this hypothesis, a CHO cell system that allows measurement of the anti-TF activity of different cell surface forms of TFPI in both in vitro and in vivo assays was developed. CHO cells were stably transfected with TF creating CHO-TF cells. In contrast to wild type CHO cells, CHO-TF cells 1) generate fXa in vitro in the presence of fVIIa, fX and calcium ions, 2) migrate through matrigel in transwell assays, and 3) produce tumors in the lungs of SCID mice following tail vein injection. The ability of solution phase TFPI-alpha and TFPI-beta to inhibit TF-fVIIa mediated fXa generation on the surface of the CHO-TF cells was examined with amidolytic assays. The Ki(final) for TFPI-alpha and TFPI-beta were 5.81 nM and 21.6 nM, respectively, confirming that solution phase TFPI-beta has decreased inhibitory activity. To examine the activity of cell surface associated TFPI-beta, CHO-TF cells were co-transfected with either TFPI-beta or equal amounts of an altered form of TFPI, called K1K2K3-GPI that is similar to TFPI-alpha but lacks its basic C-terminal region. Forms of TFPI containing the basic C-terminal region with a GPI-float could not be studied because they were not expressed by the CHO cells. CHO-TF cells expressing TFPI-beta had equal inhibitory activity to that observed in CHO-TF cells with K1K2K3-GPI suggesting that TFPI-beta is a potent inhibitor of TF activity when associated with the cell surface. The activity of cell surface associated TFPI-beta was further examined in transwell migration assays. The number of cells migrating through matrigel in multiple 20X fields was averaged. In this assay, cell surface associated TFPI-beta was a potent inhibitor of TF activity. The results are as follows: wild type CHO cells—6.6+/−4.1; CHO-TF cells—98.0+/−32.5; CHO-TF cells with TFPI-beta—9.05+/−7.0; CHO-TF cells with K1K2K3-GPI—43.5+/−21.5. Migration of CHO-TF cells was blocked using argatroban, an active site directed inhibitor of thrombin (15.0+/−4.5 CHO-TF cells migrated in the presence of 100 micromolar argatroban), demonstrating that the likely mechanism for the TF-mediated cell migration is generation of thrombin with cellular activation through cleavage of protease activated receptors. In the SCID tumor model, the severity of lung tumor burden was graded as 1–4 by a pathologist blinded to the cell type injected, n=5-8 per group. Average scores were: wild type CHO cells—1.17; CHO-TF cells 2.80; CHO-TF cells with TFPI-beta—2.14; demonstrating that cell surface associated TFPI-beta is an effective inhibitor of TF activity in vivo. Thus, while TFPI-beta has limited anticoagulant activity when examined in solution phase assays in vitro, evaluation of cell surface associated TFPI-beta reveals that it is a highly effective inhibitor of TF-fVIIa activity both in vitro and in vivo. Disclosures: Mast: Novo Nordisk: Research Funding; Siemens: Speakers Bureau.

scholarly journals Crystal structure of the simian immunodeficiency virus (SIV) gp41 core: Conserved helical interactions underlie the broad inhibitory activity of gp41 peptides

1998 ◽  
Vol 95 (16) ◽  
pp. 9134-9139 ◽  
Author(s):  
Vladimir N. Malashkevich ◽  
David C. Chan ◽  
Christine T. Chutkowski ◽  
Peter S. Kim
Keyword(s):  
Crystal Structure ◽  
Viral Entry ◽  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
Coiled Coil ◽  
Gp41 Ectodomain ◽  
Peptide Analogs ◽  
Immunodeficiency Virus ◽  
Packing Interactions ◽  
Hiv 1

The gp41 subunit of the envelope protein complex from human and simian immunodeficiency viruses (HIV and SIV) mediates membrane fusion during viral entry. The crystal structure of the HIV-1 gp41 ectodomain core in its proposed fusion-active state is a six-helix bundle. Here we have reconstituted the core of the SIV gp41 ectodomain with two synthetic peptides called SIV N36 and SIV C34, which form a highly helical trimer of heterodimers. The 2.2 Å resolution crystal structure of this SIV N36/C34 complex is very similar to the analogous structure in HIV-1 gp41. In both structures, three N36 helices form a central trimeric coiled coil. Three C34 helices pack in an antiparallel orientation into highly conserved, hydrophobic grooves along the surface of this coiled coil. The conserved nature of the N36-C34 interface suggests that the HIV-1 and SIV peptides are functionally interchangeable. Indeed, a heterotypic complex between HIV-1 N36 and SIV C34 peptides is highly helical and stable. Moreover, as with HIV-1 C34, the SIV C34 peptide is a potent inhibitor of HIV-1 infection. These results identify conserved packing interactions between the N and C helices of gp41 and have implications for the development of C peptide analogs with broad inhibitory activity.

scholarly journals Carbapenem Derivatives as Potential Inhibitors of Various β-Lactamases, Including Class B Metallo-β-Lactamases

1999 ◽  
Vol 43 (10) ◽  
pp. 2497-2503 ◽  
Author(s):  
Rie Nagano ◽  
Yuka Adachi ◽  
Hideaki Imamura ◽  
Koji Yamada ◽  
Terutaka Hashizume ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
Enterobacter Cloacae ◽  
Type Ii ◽  
New Class ◽  
Class A ◽  
Characterization Study ◽  
Class B ◽  
Class C ◽  
Potential Inhibitors

ABSTRACTA variety of 1β-methylcarbapenem derivatives were screened to identify inhibitors of IMP-1 metallo-β-lactamase, a class B β-lactamase, in an automated microassay system using nitrocefin as a substrate. The structure–inhibitory-activity relationship study revealed that three types of 1β-methylcarbapenems having benzothienylthio, dithiocarbamate, or pyrrolidinylthio moieties at the C-2 position showed good inhibitory activity. Among the compounds screened, J-110,441, having a benzothienylthio moiety at the C-2 position of 1β-methylcarbapenem, was the most potent inhibitor of class B metallo-β-lactamases withKivalues of 0.0037, 0.23, 1.00, and 0.83 μM for IMP-1 encoded by theblaIMPgene, CcrA fromBacteroides fragilis, L1 fromStenotrophomonas maltophilia, and type II fromBacillus cereus, respectively. In a further characterization study, J-110,441 also showed inhibitory activity against TEM-type class A serine β-lactamase and chromosomal class C serine β-lactamase fromEnterobacter cloacaewithKivalues of 2.54 and 0.037 μM, respectively. Combining imipenem or ceftazidime with J-110,441 had a synergistic effect on the antimicrobial activity against β-lactamase-producing bacteria. Against the isolates of IMP-1-producingSerratia marcescens, the MICs of imipenem decreased to levels ranging from 1/64 to 1/4 in the presence of one-fourth of the MIC of J-110,441. AgainstE. cloacaeproducing high levels of class C β-lactamase, the MIC of ceftazidime decreased from 64 to 4 μg/ml in the presence of 4 μg of J-110,441 per ml. This is the first report to describe a new class of inhibitor of class B and class C β-lactamases including transferable IMP-1 metallo-β-lactamases.

scholarly journals Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation

2002 ◽  
Vol 157 (3) ◽  
pp. 417-427 ◽  
Author(s):  
Kristina Lindsten ◽  
Femke M.S. de Vrij ◽  
Lisette G.G.C. Verhoef ◽  
David F. Fischer ◽  
Fred W. van Leeuwen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neurodegenerative Disorders ◽  
Inhibitory Activity ◽  
Potent Inhibitor ◽  
Important Determinant ◽  
Ubiquitin Proteasome System ◽  
Inhibitory Effect ◽  
Cycle Arrest ◽  
Protein Deposits ◽  
Ubiquitin Proteasome

Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying a 19–amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB+1 is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB+1 is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB+1 may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins.

scholarly journals The study of the determinants controlling Arpp19 phosphatase-inhibitory activity reveals a new Arpp19/PP2A-B55 feedback loop

2020 ◽  
Author(s):  
Jean Claude Labbé ◽  
Suzanne Vigneron ◽  
Francisca Méchali ◽  
Perle Robert ◽  
Cindy Genoud ◽  
...  
Keyword(s):  
Cell Division ◽  
Inhibitory Activity ◽  
Temporal Pattern ◽  
Feedback Loop ◽  
Xenopus Oocytes ◽  
Potent Inhibitor ◽  
Cyclin B ◽  
Signaling Mechanism ◽  
High Affinity ◽  
Molecular Determinants

ABSTRACTArpp19 is a potent inhibitor of PP2A-B55 that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by Greatwall on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as an “unfair” competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signaling mechanism is elusive. Here, we characterized the molecular determinants conferring slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we showed that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discovered a double feed-back loop between these two phospho-sites which is essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division.

scholarly journals Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

2018 ◽  
Vol 14 ◽  
pp. 2545-2552 ◽  
Author(s):  
Nisachon Khunnawutmanotham ◽  
Cherdchai Laongthipparos ◽  
Patchreenart Saparpakorn ◽  
Nitirat Chimnoi ◽  
Supanna Techasakul
Keyword(s):  
Binding Site ◽  
Inhibitory Activity ◽  
Inhibitory Concentration ◽  
Potent Inhibitor ◽  
Docking Studies ◽  
Amide Bond ◽  
Anionic Site ◽  
Acetylcholinesterase Inhibitory Activity ◽  
Nanomolar Concentration ◽  
Target Enzyme

A series of 3-amino-6,7-dimethoxycoumarins conjugated with the N-benzylpyridinium moiety through an amide-bond linkage was synthesized and evaluated for their acetylcholinesterase inhibitory activity. A number of the benzylpyridinium derivatives exhibited potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3-difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 ± 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme.

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