scholarly journals The structural basis of the inhibition of human glycosidases by castanospermine analogues

1990 ◽  
Vol 269 (1) ◽  
pp. 227-231 ◽  
Author(s):  
B G Winchester ◽  
I Cenci di Bello ◽  
A C Richardson ◽  
R J Nash ◽  
L E Fellows ◽  
...  
Keyword(s):  
Structural Feature ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Structural Basis ◽  
Preferential Recognition ◽  
Derivatives Of ◽  
Do So

A series of epimers and deoxy derivatives of castanospermine has been synthesized to investigate the contribution of the different chiral centres to the specificity and potency of inhibition of human liver glycosidases. Castanospermine inhibits all forms of alpha- and beta-D-glucosidases, but alteration to any of the five chiral centres in castanospermine markedly decreases the inhibition. 6-Epicastanospermine, which is related to D-pyranomannose in the same way as castanospermine is to D-pyranoglucose, does not inhibit lysosomal (acidic) alpha-mannosidase, but is a good inhibitor of the cytosolic or neutral alpha-mannosidase. Conversely, 1-deoxy-6-epicastanospermine inhibits acidic alpha-mannosidase strongly, but not the neutral alpha-mannosidase. An explanation of this different inhibition based on preferential recognition of different configurations of mannose by the different forms of alpha-mannosidase is postulated. All derivatives of 6-epicastanospermine also have the minimum structural feature for the inhibition of alpha-L-fucosidase, but those with a beta-anomeric substituent do not inhibit the enzyme, or do so very weakly. 1-Deoxy-6,8a-diepicastanospermine, which has four chiral centres identical with alpha-L-fucose, is, however, a potent inhibitor of alpha-L-fucosidase (Ki 1.3 microM).

scholarly journals Inhibition of α-l-fucosidase by derivatives of deoxyfuconojirimycin and deoxymannojirimycin

1990 ◽  
Vol 265 (1) ◽  
pp. 277-282 ◽  
Author(s):  
B Winchester ◽  
C Barker ◽  
S Baines ◽  
G S Jacob ◽  
S K Namgoong ◽  
...  
Keyword(s):  
Carbon Atom ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Competitive Inhibitor ◽  
Piperidine Ring ◽  
Structural Requirement ◽  
Ph Dependency ◽  
Structural Analogues ◽  
Hydroxy Groups ◽  
Derivatives Of

Deoxyfuconojirimycin (1,5-dideoxy-1,5-imino-L-fucitol) is a potent, specific and competitive inhibitor (Ki 1 x 10(-8) M) of human liver alpha-L-fucosidase (EC 3.2.1.51). Six structural analogues of this compound were synthesized and tested for their ability to inhibit alpha-L-fucosidase and other human liver glycosidases. It is concluded that the minimum structural requirement for inhibition of alpha-L-fucosidase is the correct configuration of the hydroxy groups at the piperidine ring carbon atoms 2, 3 and 4. Different substituents in either configuration at carbon atom 1 (i.e. 1 alpha- and beta-homofuconojirimycins) and at carbon atom 5 may alter the potency but do not destroy the inhibition of alpha-L-fucosidase. The pH-dependency of the inhibition by these amino sugars suggests very strongly that inhibition results from the formation of an ion-pair between the protonated inhibitor and a carboxylate group in the active site of the enzyme. Deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol) is also a more potent inhibitor of alpha-L-fucosidase than of alpha-D-mannosidase. This can be explained by viewing deoxymannojirimycin as beta-L-homofuconojirimycin lacking the 5-methyl group. Conversely, beta-L-homo analogues of fuconojirimycin can also be regarded as derivatives of deoxymannojirimycin. This has permitted deductions to be made about the structural requirements of inhibitors of alpha- and beta-D-mannosidases.

scholarly journals The structural basis of the inhibition of human α-mannosidases by azafuranose analogues of mannose

1993 ◽  
Vol 290 (3) ◽  
pp. 743-749 ◽  
Author(s):  
B Winchester ◽  
S al Daher ◽  
N C Carpenter ◽  
I Cenci di Bello ◽  
S S Choi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Human Fibroblasts ◽  
Structural Basis ◽  
Multiple Forms ◽  
Storage Products ◽  
Normal Human ◽  
Ring Nitrogen

Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.

Synthesis, Docking Studies into CDK-2 and Anticancer Activity of New Derivatives Based Pyrimidine Scaffold and Their Derived Glycosides

2019 ◽  
Vol 19 (13) ◽  
pp. 1093-1110 ◽  
Author(s):  
Adel A.H. Abdel Rahman ◽  
Ibrahim F. Nassar ◽  
Amira K.F. Shaban ◽  
Dina S. EL-Kady ◽  
Hanem M. Awad ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Human Liver ◽  
Docking Studies ◽  
Cyclin Dependent Kinase ◽  
Binding Interaction ◽  
Enzyme Active Site ◽  
Human Liver Cancer ◽  
Amino Derivatives ◽  
Activity Behavior ◽  
Derivatives Of

Background & Objective:New diaryl-substituted pyrimidinedione compounds, their thioxo derivatives as well as their bicyclic thiazole compounds were synthesized and characterized.Methods:The glycosylamino derivatives of the synthesized disubstituted derivatives of the pyrimidine scaffold were also prepared via reaction of the N3-amino derivatives with a number of monosaccharides followed by acetylation.Results:The anticancer activity of the synthesized compounds was studied against human liver cancer (HepG2) and RPE-1cell lines. Compounds 2a, 2b, 3a and 12 showed potent activities with IC50 results comparable to that of doxorubicin.Conclusion:Docking investigations into Cyclin-dependent kinase 2 (CDK-2) enzyme, a potential target for cancer medication, were also reported showing the possible binding interaction into the enzyme active site to support their activity behavior.

The Interactions of adenylates with allosteric citrate synthase

1979 ◽  
Vol 57 (5) ◽  
pp. 385-395 ◽  
Author(s):  
Michael M. Talgoy ◽  
Harry W. Duckworth
Keyword(s):  
Coenzyme A ◽  
Citrate Synthase ◽  
Potent Inhibitor ◽  
Sulfhydryl Group ◽  
Fluorescence Technique ◽  
Allosteric Site ◽  
Acetyl Coenzyme A ◽  
Nitrobenzoic Acid ◽  
Adenylic Acid ◽  
Derivatives Of

Evidence is presented that a number of derivatives of adenylic acid may bind to the allosteric NADH binding site of Escherichia coli citrate synthase. This evidence includes the facts that all the adenylates inhibit NADH binding in a competitive manner and that those which have been tested protect an enzyme sulfhydryl group from reaction with 5,5′-dithiobis-(2-nitrobenzoic acid) in the same way that NADH does. However, whereas NADH is a potent inhibitor of citrate synthase, most of the adenylates are activators. The best activator, ADP-ribose, increases the affinity of the enzyme for the substrate, acetyl-CoA, and saturates the enzyme in a sigmoid manner. A fluorescence technique, involving the displacement of 8-anilino-1-naphthalenesulfonate from its complex with citrate synthase, is used to obtain saturation curves for several nucleotides under nonassay conditions. It is found that acetyl-coenzyme A, coenzyme A, and ADP-ribose all bind to the enzyme cooperatively, and that the binding of each becomes tighter in the presence of KCl the activator, and oxaloacetic acid (OAA), the second substrate. Another inhibitor, α-ketoglutarate, can compete with OAA in the absence of KClbut not in its presence. The nature of the allosteric site of citrate synthase, and the modes of action of several activators and inhibitors, are discussed in the light of this evidence.

Hymenolepis diminuta: metacestode-induced reduction in the synthesis of the yolk protein, vitellogenin, in the fat body of Tenebrio molitor

Parasitology ◽  
1996 ◽  
Vol 112 (4) ◽  
pp. 429-436 ◽  
Author(s):  
T. J. Webb ◽  
H. Hurd
Keyword(s):  
Post Infection ◽  
Fat Body ◽  
Potent Inhibitor ◽  
Tenebrio Molitor ◽  
Hymenolepis Diminuta ◽  
Vitellogenin Synthesis ◽  
Specific Stage ◽  
Fat Bodies ◽  
Do So

SUMMARYVitellogenin synthesis by the fat body has been monitored using in vitro culture and immunoprecipitation. This system was found to be efficient for measuring vitellogenin production in both non-infected Tenebrio molitor and those infected with Hymenolepis diminuta. In fat bodies from infected beetles, vitellogenin production was decreased by up to 75% (day 24 post-infection) and, at all times investigated, vitellogenin synthesis was significantly below control levels (days 3–30 post-infection). Incubating fat bodies from control insects with isolated metacestodes indicated that this may be a direct effect by the parasite which is developmental stage-specific. Stage II, but not stage III–IV, nor heat-killed parasites could bring about this decrease in vitellogenin. In addition, these effects may be density dependent within the range of 2–20 parasites per fat body; only 2 metacestodes were necessary to cause a significant decrease. Since metacestodes do not take up vitellogenin, nor limit the amount of [14C] leucine available to the fat body for vitellogenin production, it is conceivable that the parasite produces a potent inhibitor of vitellogenin synthesis, or a molecule which induces cells within the fat body to do so.

Nojirimycin-A potent inhibitor of purified lysosomal alpha-glucosidase from human liver

1982 ◽  
Vol 107 (4) ◽  
pp. 1490-1496 ◽  
Author(s):  
James P. Chambers ◽  
Alan D. Elbein ◽  
Julian C. Williams
Keyword(s):  
Human Liver ◽  
Potent Inhibitor ◽  
Alpha Glucosidase

scholarly journals Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Lendelle Raymond ◽  
Nikita Rayani ◽  
Grace Polson ◽  
Kylie Sikorski ◽  
Ailin Lian ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
High Throughput Screening ◽  
Human Liver ◽  
Potent Inhibitor ◽  
Cytochrome P450s ◽  
Third Generation ◽  
Weak Inhibitor ◽  
Liver Cytochrome ◽  
Ic50 Values ◽  
Screening Assays

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

Fractional derivatives of multidimensional Colombeau generalized stochastic processes

2013 ◽  
Vol 16 (4) ◽  
Author(s):  
Danijela Rajter-Ćirić ◽  
Mirjana Stojanović
Keyword(s):  
Stochastic Process ◽  
Fractional Derivative ◽  
Stochastic Processes ◽  
Compact Support ◽  
Caputo Fractional Derivative ◽  
Fractional Derivatives ◽  
One Dimensional ◽  
Compactly Supported ◽  
Derivatives Of ◽  
Do So

AbstractWe consider fractional derivatives of a Colombeau generalized stochastic process G defined on ℝn. We first introduce the Caputo fractional derivative of a one-dimensional Colombeau generalized stochastic process and then generalize the procedure to the Caputo partial fractional derivatives of a multidimensional Colombeau generalized stochastic process. To do so, the Colombeau generalized stochastic process G has to have a compact support. We prove that an arbitrary Caputo partial fractional derivative of a compactly supported Colombeau generalized stochastic process is a Colombeau generalized stochastic process itself, but not necessarily with a compact support.

Genetic polymorphisms in human liver phenol sulfotransferases involved in the bioactivation of N-hydroxy derivatives of carcinogenic arylamines and heterocyclic amines

1998 ◽  
Vol 109 (1-3) ◽  
pp. 237-248 ◽  
Author(s):  
Shogo Ozawa ◽  
Yong-Ming Tang ◽  
Yasushi Yamazoe ◽  
Ryuichi Kato ◽  
Nicholas P Lang ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Human Liver ◽  
Heterocyclic Amines ◽  
Derivatives Of
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