Glucosidase deoxynojirimycin

In the 1-deoxynojirimycin series, the 2- (87), the 3- (97), and the 6-deoxyfluoro compound 91 (Scheme 24) were compared with the parent compound against a set of standard glucosidases.232 3-Deoxyfluoro (97, A) 0.35 pM) as well as 6-deoxyfluoro (91, 0.4 pM) derivatives exhibited a 40-fold decreased power with the a-glucosidase from rice (GH 31) as compared with the parent compound 2 (K, 0.01 pM at pH 6). Fagomine (1,2-dideoxynojirimycin, 3) was reported to have an IC50 of 320 pM with this enzyme.205... 

Not unexpectedly by comparison with the monofluorinated 1-deoxynojirimycin derivatives, the 4,4-difluoro derivative 102 (Scheme 26) was found to be inactive with almond (l-glucosidase and the a-glucosidase from yeast.227 Equally inactive with these enzymes was the 3,3-difluoro compound 105 (Scheme 26).228 It is noteworthy that the 4,4-difluoro derivative of 1-deoxymannojirimycin, 103 (pAfa 5.3) turned out a good inhibitor of the (1-glucosidase from almonds (K, 45 pM, at pH 6.8 2 47 pM) and remained unprotonated and active at pH 5 (K, 92 pM 2 Kt 300 pM)227... 

Fig. 6. Superposition of ligands 1-deoxynojirimycin 2 (yellow, PDB 2J77) and castanospermine 8 (green, PDB 2CBU) bound to Thermotoga maritima p-glucosidase. The ring nitrogen atoms, all hydroxyl groups in the pyranoid rings, as well as 0-1 (8) and the primary 0-6 (2), respectively, are closely matched.

Scheme 33) was highly effective.357 Nonpolar Aralkyl substituents containing alkyl-silyl or arylsilyl moieties in such 1-deoxynojirimycin derivatives as 183 were shown to increase the inhibitory activities on human intestinal oc-glucosidases, with short-and medium-length chains containing a double bond (184) giving best results.358... 

In contrast to the inactive parent compound 2, inhibition of glycoprotein-processing oc-glucosidases was also found by Butters and coworkers for 1-deoxynojirimycin derivatives having phenylalkyl substituents of medium chain lengths (C4—C6) at the ring nitrogen atom.359... 

A-Butyl-l-deoxynojirimycin (131) HO VsY N Vv HO OH Acid P-glucosidase, human (GH 30) 2V3D 268... 

K. M. Osiecki-Newman, D. Fabbro, T. Dinur, S. Boas, S. Gatt, G. Legler, R. J. Desnick, and G. A. Grabowski, Human acid p-glucosidase Affinity purification of the normal placental and Gaucher disease splenic enzymes on N-alkyl-deoxynojirimycin-sepharose, Enzyme, 35 (1986) 147-153. 

K. Dax, V. Grassberger, and A. E. Stiitz, Simple synthesis of l,5,6-trideoxy-l,5-imino-D-glucitol, the first fluorine-containing derivative of glucosidase inhibitor 1-deoxynojirimycin, J. Carbohydr. Chem., 9 (1990) 903-908. 

S. M. Andersen, M. Ebner, C. W. Ekhart, G. Gradnig, G. Legler, I. Lundt, A. E. Stiitz, S. G. Withers, and T. Wrodnigg, Two isosteric fluorinated derivatives of the powerful glucosidase inhibitors, 1-deoxynojirimycin and 2,5-dideoxy-2,5-imino-D-mannitol Syntheses and glycosidase inhibitory activities of l,2,5-trideoxy-2-fluoro-l,5-imino-D-glucitol and of l,2,5-trideoxy-l-fluoro-2,5-imino-D-mannitol, Carbohydr. Res., 301 (1997) 155-166. 

B. Brumshtein, H. M. Greenblatt, T. D. Butters, Y. Shaaltiel, D. Aviezer, I. Sihnan, A. H. Futerman, and J. L. Sussman, Crystal structures of complexes of iV-butyl- and iV-nonyl-deoxynojirimycin bound to acid P-glucosidase. Insights into the mechanism of chemical chaperone action in Gaucher disease,... 

D. S. Alonzi, R. A. Dwek, and T. D. Butters, Improved cellular inhibitors for glycoprotein processing a-glucosidases Biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins, Tetrahedron Asymmetry, 20 (2009) 897-901. 

In 1987 2,6-dideoxy-2,6-imino-D-g(ycero-L-gM/o-heptitol (14), a chain-extended derivative of 1-deoxynojirimycin, was synthesized as a potential glucosidase inhibitor [50] and soon thereafter extracted from the leaves of the Panamesian plant Omphalea diandra L [51]. Coined a-homonojirimycin by the discoverers, this novel type of inhibitor exhibited pronounced activity against gluco-... 

Various open-chain analogues [74] of 1-deoxynojirimycin, such as (32), were synthesized as potential glucosidase inhibitors and, surprisingly, exhibited good... 

Heteroatom-substituted carbohydrates are efficiently assembled by the enzymatic aldol condensation of DHAP with an appropriately appended aldehyde. Iminocyclitols that are inhibitors of glycosidases, such as deoxynojirimycin and deoxymannojirimycin, are simply prepared by condensation of azo-substituted aldehydes under the FDP protocol followed by dephosphorylation and palladium mediated reductive animation (Scheme 5.18a).39 In addition a number of polyhydroxylated pyrrolidines that are efficient glucosidase inhibitors have been synthesized by this chemo-enzymatic strategy (Scheme 5.18 ).1" 30,40 If the palladium mediated hydrogenation is done in the presence of hydrochloric acid, an amino-sugar intermediate is formed as its hydrochloride salt. Treatment with base then forms polyhydroxylated imines, instead of iminocyclitols (Scheme 5.19).41... 

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