Synthesis and evaluation of N-alkylated analogues of aza-galacto-fagomine – potential pharmacological chaperones for Krabbe disease

2016 ◽  
Vol 14 (36) ◽  
pp. 8545-8556 ◽  
Author(s):  
Agnete H. Viuff ◽  
Henrik H. Jensen
Keyword(s):  
Krabbe Disease ◽  
Glycosidase Inhibitors ◽  
Inhibitory Potency ◽  
Pharmacological Chaperones

Seven novel alkylated or acylated analogues of hexahydropyridazine aza-galacto-fagomine (AGF) was prepared and studied as glycosidase inhibitors with the aim of increasing inhibitory potency and selectivity.

scholarly journals Azasugar inhibitors as pharmacological chaperones for Krabbe disease

2015 ◽  
Vol 6 (5) ◽  
pp. 3075-3086 ◽  
Author(s):  
Chris H. Hill ◽  
Agnete H. Viuff ◽  
Samantha J. Spratley ◽  
Stéphane Salamone ◽  
Stig H. Christensen ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Krabbe Disease ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones

Modified azasugar molecules have been synthesized and characterized as excellent pharmacological chaperone candidates to treat the neurodegenerative disorder Krabbe disease.

scholarly journals Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 4025
Author(s):  
Patrick Weber ◽  
Martin Thonhofer ◽  
Summer Averill ◽  
Gideon J. Davies ◽  
Andres Gonzalez Santana ◽  
...  
Keyword(s):  
Lysosomal Storage Diseases ◽  
Hydroxyl Group ◽  
Glycosidase Inhibitors ◽  
Lysosomal Storage ◽  
X Ray ◽  
Pharmacological Chaperones ◽  
X Ray Crystallography ◽  
Structure Activity ◽  
New Compounds ◽  
Derivatives Of

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.

Polycyclitols — Novel conduritol and carbasugar hybrids as new glycosidase inhibitors

2005 ◽  
Vol 83 (6-7) ◽  
pp. 581-594 ◽  
Author(s):  
Goverdhan Mehta ◽  
Senaiar S Ramesh
Keyword(s):  
Key Words ◽  
Preliminary Investigation ◽  
Diels Alder ◽  
Glycosidase Inhibitors ◽  
Selective Inhibitors ◽  
Inhibitory Potency ◽  
Thermally Induced

A family of novel carbasugar analogues (bicyclitols) based on cis-hydrindane and cis-decalin frameworks has been conceptualized. These novel entities can be regarded as conduritol and carbasugar hybrids. Syntheses of these polyhydroxylated entities have been achieved in stereo- and regioselective manners, starting from the readily available Diels–Alder adducts of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and appropriate dienophiles like cyclopentadiene or p-benzoquinone, that embody a masked 7-ketonorbornenone moiety. Thermally induced chelotropic elimination of CO from the appropriately functionalized 7-ketonorbornenone derivatives to deliver annulated bicyclic 1,3-cyclohexadiene derivatives was the key step in this synthetic endeavor. Further oxy-functionalization of the 1,3-cyclohexadiene moiety delivered the targeted polycyclitols. A preliminary investigation of the glycosidase inhibitory potency of these bicyclitols, identified compounds 18 and 54 as potent and selective inhibitors of α-glucosidase (yeast).Key words: carbasugar, conduritol, glycomimics, glycosidase inhibitors.

scholarly journals Fluorous Iminoalditols: A New Family of Glycosidase Inhibitors and Pharmacological Chaperones

ChemBioChem ◽  
2010 ◽  
Vol 11 (14) ◽  
pp. 2026-2033 ◽  
Author(s):  
Georg Schitter ◽  
Andreas J. Steiner ◽  
Gerit Pototschnig ◽  
Elisabeth Scheucher ◽  
Martin Thonhofer ◽  
...  
Keyword(s):  
Glycosidase Inhibitors ◽  
Pharmacological Chaperones ◽  
New Family

Hematopoietic Stem Cell Transplantation for Late-Onset Krabbe Disease

2015 ◽  
Vol 46 (S 01) ◽  
Author(s):  
A. Bley ◽  
U. Löbel ◽  
M. Nickel ◽  
A. Ohlenbusch ◽  
J. Denecke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Late Onset ◽  
Krabbe Disease ◽  
Hematopoietic Stem

Heparin Counteracts the Antiaggregating Effect of Prostacyclin by Potentiating Platelet Aggregation

1983 ◽  
Vol 49 (02) ◽  
pp. 081-083 ◽  
Author(s):  
Vittorio Bertelé ◽  
Maria Carla Roncaglioni ◽  
Maria Benedetta Donati ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Specific Interaction ◽  
Inhibitory Effect ◽  
Effective Inhibitor ◽  
Inhibitory Potency ◽  
Human Platelet Aggregation

SummaryIt has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1, and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

MR imaging and single proton spectroscopy in siblings with late onset krabbe disease

2008 ◽  
Vol 39 (01) ◽  
Author(s):  
U Gruber-Sedlmayr ◽  
M Brunner-Krainz ◽  
E Sorantin ◽  
W Sauseng ◽  
B Plecko
Keyword(s):  
Mr Imaging ◽  
Late Onset ◽  
Krabbe Disease ◽  
Proton Spectroscopy ◽  
Single Proton
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