100991-91-1Relevant articles and documents
Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors
Vandenberg, Richard J.B.H.N.,Vanrijssel, Erwin R.,Ferraz, Maria Joao,Houben, Judith,Strijland, Anneke,Donker-Koopman, Wilma E.,Wennekes, Tom,Bonger, Kimberly M.,Ghisaidoobe, Amar B. T.,Hoogendoorn, Sascha,Vandermarel, Gijsbert A.,Codée, Jeroen D. C.,Overkleeft, Herman S.,Aerts, Johannes M. F. G.
, p. 2042 - 2062 (2015/12/23)
Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism - glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2) - is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39-compound library does not contain new GCS inhibitors; however, a potent (200nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator. Taking the best of both: Two established glucosylceramide synthase (GCS) inhibitors were merged via convergent synthesis to obtain hybrid compounds. Members of this 39-compound library have characteristics of both parent GCS inhibitors. No new GCS inhibitors were established, but a potent (200nm) acid glucosylceramidase (GBA1) inhibitor was identified. This adamantanemethyloxypenanoic acid pyrrolidene-substituted derivative of eliglustat can serve as a lead for further biomedical development of selective GBA1 modulators.
Synthesis from D-lyxonolactone of 1,4-dideoxy-1,4-imino-L-arabinitol, a glucosidase inhibitor with in vitro anti-viral activity
Behling, James R.,Campbell, Arthur L.,Babiak, Kevin A.,Ng, John S.,Medic, John,Farid, Payman,Fleet, George W. J.
, p. 3359 - 3366 (2007/10/02)
Benzylidenation is the only protection required in a 7 step synthesis of the hydrochloride of 1,4-dideoxy-1,4-imino-L-arabinitol from D-lxyonolactone in an overall yield of 21%.
A CONVENIENT SYNTHESIS OF 4-AMINO-4-DEOXY-L-ARABINOSE AND ITS REDUCTION PRODUCT, 1,4-DIDEOXY-1,4-IMINO-L-ARABINITOL
Naleway, John J.,Raetz, Christian R. H.,Anderson, Laurens
, p. 199 - 210 (2007/10/02)
Methyl β-D-xylopyranoside in a mixture of N,N-dimethylformamide and 2-methoxypropene containing a little hydrogen chloride gave preponderantly the 2,3-O-isopropylidene derivative, which was readily converted into its 4-trifluoromethanesulfonate.The facile displacement of the triflate group gave a 4-azido-4-deoxy-α-L-arabinopyranoside derivative, and this, on mild acid treatment, was hydrolyzed to the 2,3-diol, or under more vigorous conditions to 4-azido-4-deoxy-L-arabinose.Methyl 2,3-di-O-acetyl-4-azido-4-deoxy-α-L-arabinopyranoside, from the diol, appears (1H-n.m.r. data) to exist as an equilibrating mixture of the 4C1 and 1C4 conformers in chloroform solution.The reduction of the azido sugar by hydrogen over Pd/C in 6M HCl yielded 4-amino-4-deoxy-L-arabinose as its hydrochloride; in 0.1M HCl, further reactions occurred to give 1,4-dideoxy-1,4-imino-L-arabinitol as the final product.The aminodeoxypentose from lipid A precursor IIA, isolated from a Salmonella mutant by Raetz et al. in 1985, was shown to be identical with the synthetic aminoarabinose by t.l.c., 1H-n.m.r. spectroscopy, and g.l.c. of the acetylated reduction products.
