193540-72-6Relevant articles and documents
Synthesis of 1-azagalactofagomine, a potent galactosidase inhibitor
Jensen, Henrik Helligso,Bols, Mikael
, p. 905 - 909 (2001)
1-Azagalactofagomine [(+)-(3R,4S,5R)-4,5-Dihydroxy-3-(hydroxymethyl)hexahydropyridazine, 2] was synthesised from achiral starting materials in a chemoenzymic synthesis. The racemic Diels-Alder adduct (2-hydroxymethyl-8-methyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione, 5) from addition of pentadienol to 4-methyl-1,2,4-triazoline3,5-dione was resolved using lipase R-catalysed acetylation. The acetate [(S)-2-acetoxymethyl-8-methyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione, 6] was saponified and treated with MCPBA to give a majority of the syn epoxide [(2R,3S,4R)-3,4-epoxy-2-hydroxymethyl-8-methyl-1,6,8-triazabicyclo[4.3.0]nonane- 7,9-dione, 7]. This isomer was subjected to epoxide opening with HI followed by a Woodward reaction-like displacement of the iodide with water and peracetylation to give an all-syn triacetate [(2R,3S,4R)-3,4-diacetoxy-2-acetoxymethyl-1,6,8-triazabicyclo[4.3.0]nonane-7,9-d ione, 11]. Finally deacetylation and hydrazinolysis gave 2. The pKa of 2 was determined to be 5.7. 1-Azagalactofagomine was found to be a potent competitive galactosidase inhibitor. The inhibition constants, Ki, were 40, 300 and 7800 nM versus β-galactosidase from Aspergillus oryzae, Eschinchia coli and Saccharomyces fragilis, respectively, and 280 nM vs. α-galactosidase from green coffee beans.
Synthesis and evaluation of α-, β-glucosidase inhibition of 1-N-carboxamide-1-azafagomines and 5-epi-1-azafagomines
Mendes, Raquel,Duarte, Vera C.M.,Gil Fortes, António,Alves, Maria J.
, p. 52 - 57 (2014)
1-N-Carboxamide 1-azafagomines and 5-epi-1-azafagomines were obtained from 1-azafagomine and 5-epi-1-azafagomine. The hydroxyl groups and the N-2 pyridazine position were protected prior to reaction with different isocyanates to form ureas. Protective gro
A short stereoselective synthesis of (+)-aza-galacto-fagomine (AGF)
Trajkovic, Jasna Marjanovic,Ferjancic, Zorana,Saicic, Radomir N.
, p. 2629 - 2632 (2017/04/10)
A catalytic asymmetric synthesis of (+)-aza-galacto-fagomine (AGF) – the most promising compound for the pharmacological chaperone therapy of Krabbe disease – was accomplished in six steps, in 14% overall yield. The synthesis hinges on the combination of
Azasugar inhibitors as pharmacological chaperones for Krabbe disease
Hill, Chris H.,Viuff, Agnete H.,Spratley, Samantha J.,Salamone, Stéphane,Christensen, Stig H.,Read, Randy J.,Moriarty, Nigel W.,Jensen, Henrik H.,Deane, Janet E.
, p. 3075 - 3086 (2015/09/08)
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure-activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.
Advances in the synthesis of homochiral (-)-1-azafagomine and (+)-5-epi-1-azafagomine. 1-N-phenyl carboxamide derivatives of both enantiomers of 1-azafagomine: Leads for the synthesis of active α-glycosidase inhibitors.
Alves, M. Jose,Costa, Flora T.,Duarte, Vera C. M.,Fortes, Antonio Gil,Martins, Jose A.,Micaelo, Nuno M.
scheme or table, p. 9584 - 9592 (2012/01/03)
A new expeditious preparation of homochiral ( - )-1-azafagomine and (+)-5-epi-1-azafagomine has been devised. Stoodley's diastereoselective cycloaddition of dienes bearing a 2,3,4,6-tetraacetyl glucosyl chiral auxiliary to 4-phenyl-1,2,4-triazole-3,5-dione was merged with Bols's protocol for functionalizing alkenes into molecules bearing a glucosyl framework. Homochiral (+)-5-epi-1-azafagomine was synthetized for the first time. Partial reductive cleavage of the phenyltriazolidinone moiety afforded new homochiral 1-N-phenyl carboxamide derivatives of 1-azafagomine. Both enantiomers of these derivatives were synthetized and tested, displaying a very good enzymatic inhibition toward baker's yeast α-glucosidase. The molecular recognition mechanism of the 1-N-phenyl carboxamide derivative of 1-azafagomine by α-glucosidase from baker's yeast was studied by molecular modeling. The efficient packing of the aromatic ring of the 1-N-phenyl carboxamide moiety into a hydrophobic subsite (pocket) in the enzyme's active site seems to be responsible for the improved binding affinity in relation to underivatized ( - )-1-azafagomine and (+)-1-azafagomine.
Improvements to the synthesis of isofagomine, noeuromycin, azafagomine, and isofagomine lactam, and a synthesis of azanoeuromycin and guanidine isofagomine
Meloncelli, Peter J.,Stick, Robert V.
, p. 827 - 833 (2007/10/03)
Improvements in the preparation of a key imidazylate and the reduction of the derived nitrile have led to more efficient syntheses of isofagomine, noeuromycin, azafagomine, and isofagomine lactam. As well, a precursor of azafagomine has been converted int
Enantiospecific synthesis of 1-azafagomine
Ernholt,Thomsen,Lohse,Plesner,Jensen,Hazell,Liang,Jakobsen,Bols
, p. 278 - 287 (2007/10/03)
For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1- deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)- 1). By a similar sequence of reactions, L-xylose was converted to (-)-1- azafagomine ((-)1). Enzymatic and other routes to optically pure 1- azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond β-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 104 M-1 s-1 and 0.011 s-1, respectively, yielding K(i) = 0.33 μM.
Chemoenzymatic synthesis of enantiopure 1-azafagomine
Liang, Xifu,Bols, Mikael
, p. 8485 - 8488 (2007/10/03)
A new chemoenzymatic synthesis of both enantiomeric forms of the glycosidase inhibitor 1-azafagomine (1) is reported. The synthesis starts from the achiral starting materials pentadienol and methylurazol with the key steps being a hetero-Diels-Alder reaction followed by a lipase R/Novozym 435- catalyzed enantioselective esterification of the Diels-Alder adduct.
Synthesis of (+)-azafagomine from D-xylose
Ernholt, Bettina V.,Thomsen, Ib B.,Jensen, Kenneth B.,Bols, Mikael
, p. 701 - 704 (2007/10/03)
L-glucose resembling enantiomer of the racemic glycosidase inhibitor azafagomine was synthesised from D-xylose and found to be inactive.
1-Azafagomine: A hydroxyhexahydropyridazine that potently inhibits enzymatic glycoside cleavage
Bols, Mikael,Hazell, Rita G.,Thomsen, Ib B.
, p. 940 - 947 (2007/10/03)
(3,4-trans-4,5-trans)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine (16) was synthesized in four steps from 2,4-pentadienol (22) and 4-phenyltriazolin-3,5-dione (18) in an overall yield of 32%. In the first step a Diels Alder reaction between 18 and 22 gave (±)-2-hydroxymethyl-8-phenyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3-trans-3,4-trans)-3,4-dihydroxy-2-hydroxymethyl-8-phenyl-1,6,8-triazabicy clo[4.3.0]-nonane-7,9-dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of χ-and β-glucosidase, isomaltase and glycogen phosphorylase, while galactosidases and χ-mannosidase were not inhibited. The inhibition of β-glucosidase is independent of pH, and was found to be due to unprotonated 16.
