275363-98-9Relevant articles and documents
Synthesis of Isofagomine Derivatives as New Fluorescence pH Indicators/Glycosidase Inhibitors
Bogh, Sidsel Ammitzb?ll,Bols, Mikael,Laursen, Bo W.,Poulsen, Jens Christian Navarro,Wang, Bo
, (2020/07/04)
Inhibitor protonation of azasugars of the isofagomine type when bound to enzyme can be investigated using photon induced electron transfer (PET) quenching of an attached fluorophore. For this purpose, Isofagomine, iso-d-galacto-fagomine, and iso-l-gulo-fagomine were converted to N-(10-chloroanthracenenyl-9-alkyl) derivatives where the alkyl group contained one, two, or three methylene groups. The new derivatives displayed pH dependent fluorescence; as the ammonium forms they were fluorescent, while 90–99 percent of the fluorescence was quenched in the amine forms. The 3 isofagomine derivatives were competitive inhibitors of T. Maritima Ι-glucosidase with Ki values from 0.37–4.6ΤM. Similarly, the iso-d-galacto-fagomines inhibited A. Niger Ι-galactosidase with Ki values from 63–2000 nm. When bound to the enzymes the inhibitors displayed between 1–15 percent fluorescence.
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.
A divergent approach for the synthesis of some polyhydroxy pyrrolidines and piperidines from ribosylamine
Chirke, Sahadev S.,Rajender, Anugula,Rao, Batchu Venkateswara
, p. 103 - 109 (2014/01/06)
A simple and efficient synthesis of 1,4-dideoxy-1,4-imino-d-ribitol, 1,4-dideoxy-1,4-imino-l-lyxitol, N-benzyl derivative of d-ribitol, 3,4,5-trihydroxy-piperidine, l-4-epi-isofagomine and d-3-epi-isofagomine, which are glycosidase inhibitors has been described from the commercially available d-ribose as a starting material.
Iminosugar-based galactoside mimics as inhibitors of galactocerebrosidase: SAR studies and comparison with other lysosomal galactosidases
Biela-Banas, Anna,Ouladi, Farah,Front, Sophie,Gallienne, Estelle,Ikeda-Obatake, Kyoko,Asano, Naoki,Wenger, David A.,Martin, Olivier R.
, p. 2647 - 2652 (2015/02/19)
Several families of iminosugar-based galactoside mimics were designed, synthesized, and evaluated as galactocerebrosidase (GALC) inhibitors. They were also tested as inhibitors of lysosomal β- and α-galactosidases in order to find new potent and selective pharmacological chaperones for treatment of the lysosomal storage disorder, Krabbe disease. Whereas 1-C-alkyl imino-l-arabinitols are totally inactive toward the three enzymes, 1-C-alkyl imino-L-galactitols were found to be active only toward α-galactosidase A. Finally, 1-N-iminosugars provided the best results, as 4-epi-isofagomine was found to be a good inhibitor of both lysosomal β-galactosidase and GALC. Further elaboration of this structure is required to achieve selectivity between these two galactosidases.
Synthesis of isofagomine and some new azasugars as glycosidase inhibitors from d-mannitol derived nitroolefins
Roy, Rashmi,Kancharla, Pavan K.,Reddy, Y. Suman,Brar, Anita,Vankar
, p. 1502 - 1513 (2013/12/04)
The synthesis of isofagomine, epi-isofagomine and isofagomine analogues along with some new azasugars from two different vinyl nitro compounds, that were derived from d-mannitol, has been carried out. Two different synthetic strategies were followed for e
Synthesis of l-3-epi-isofagomine, its homo-, n-butyl and bicyclic analogues from d-glucose as glycosidase inhibitors
Mallick, Asadulla,John Pal,Vankar, Yashwant D.
supporting information, p. 6549 - 6552 (2013/11/19)
Synthesis of l-3-epi-isofagomine, its homo-, n-butyl derivatives and its bicyclic analogue as potent glycosidase inhibitor has been achieved from readily available d-glucose. Inhibition of some commercially available glycosidases was also carried out with
Synthesis of (+)-isofagomine
Kulkarni, Mukund G.,Shaikh, Yunnus B.,Birhade, Deekshaputra R.,Borhade, Ajit S.,Chavhan, Sanjay W.,Dhondge, Attrimuni P.,Gaikwad, Dnyaneshwar D.,Dhatrak, Nagorao R.
, p. 1234 - 1237 (2012/11/07)
The synthesis of (+)-isofagomine 1 using 4-pentenol 3 as a chiral precursor is described herein.
Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars
Reddy, Y. Suman,Kancharla, Pavan K.,Roy, Rashmi,Vankar, Yashwant D.
, p. 2760 - 2773 (2012/11/07)
Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors. The Royal Society of Chemistry 2012.
Asymmetric synthesis of polyhydroxylated N -alkoxypiperidines by ring-closing double reductive amination: Facile preparation of isofagomine and analogues
Malik, Gaelle,Guinchard, Xavier,Crich, David
, p. 596 - 599 (2012/02/16)
A de novo synthesis of novel polyhydroxylated N-alkoxypiperidines based on the ring-closing double reductive amination of 1,5-dialdehydes, obtained by oxidative cleavage of cyclopentene derivatives, with O-substituted hydroxylamines is reported. Isofagomine was accessed by cleavage of the N-O bond of an N-alkoxypiperidine.
Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors
Kato, Atsushi,Miyauchi, Saori,Kato, Noriko,Nash, Robert J.,Yoshimura, Yuichi,Nakagome, Izumi,Hirono, Shuichi,Takahata, Hiroki,Adachi, Isao
experimental part, p. 3558 - 3568 (2011/07/09)
We report the structure-activity relationship of a series of d-, and l-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosida
