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Abstract: 3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-d-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited β-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1mM). [Copyright &y& Elsevier]

Abstract: A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP. [Copyright &y& Elsevier]

Abstract: Polyhydroxy 4-azaspiro[2.4]heptane derivatives (spirocyclopropyl iminosugars) were prepared in four to six steps from readily available protected aldoses. The key step of the reaction sequence involves a titanium-mediated aminocyclopropanation of glycononitriles with subsequent cyclization. Five new polyhydroxypyrrolidines so-obtained have been evaluated for their ability to inhibit 16 glycosidases. One of them exhibits selective inhibition of α-l-fucosidase from bovine kidney (K i =1.6μM, competitive). [Copyright &y& Elsevier]

Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino-l-erythrose and 4-amino-5-deoxy-l-ribose series were synthesised by asymmetric hetero-Diels–Alder reaction followed by chemical transformations. 4-Amino-4-deoxy-l-erythrose and 4-amino-4,5-dideoxy-l-ribose were potent β-d-glucosidase, α-d-mannosidase, α- and β-d-galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α-d-mannosidase. [Copyright &y& Elsevier]

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1′,2′)-dihydroxyethyl substituent of homoDMDP with –C 4 F 9 proved detrimental for enzyme binding, introduction of a –C 3 F 7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast. [ABSTRACT FROM AUTHOR]

A series of diastereomeric tetrahydroxylated azepanes featuring a carboxymethyl group at the pseudo-anomeric position have been synthesized from a common unsaturated intermediate. Syn - and anti -dihydroxylation reactions were achieved to yield the target compounds after efficient one-step deprotection of carbamate, ester and acetonide groups simultaneously. Screening of these polyhydroxylated azepanes toward a range of commercially available glycosidases was performed and one of the stereoisomers showed potent and selective inhibition toward β-galactosidase (IC 50 = 21 μM). [ABSTRACT FROM AUTHOR]

Ten phenylalkyl-substituted iminosugars ( 1 – 10 ) and a cinnamic acid derived glucoside ( 11 ) were isolated from the roots of Glyphaea brevis (Malvaceae). Their structures were elucidated by 1D and 2D NMR analysis, as well as by HR-ESIMS. Compounds 1 – 10 retain an unprecedented structure composed of an iminosugar-like core identified as 1-deoxyfuconojirimycin in glyphaeaside A 1 –A 4 ( 1 , 2 , 5 , 6 ), 1-deoxygalactonojirimycin in glyphaeaside B 1 –B 5 ( 3 , 4 , 7 – 9 ) or 1-deoxynojirimycin in glyphaeaside C ( 10 ), substituted by a β - d -glucopyranose in compounds 2 , 4 , 6 and 9 . These compounds feature a di-, tri- or tetra-hydroxylated nine-carbon chain at the pseudo-anomeric position, substituted by a terminal phenyl group. All alkyl C -iminosugars displayed potent and selective inhibition towards β -glucosidase with IC 50 values ranging from 0.15 to 68 μM. Compound 10 with an 1-deoxynojirimycin backbone was the most active and was found to act as a competitive inhibitor with K i = 31 nM, therefore emerging as one of the most potent inhibitor of β -glucosidase reported to date. Inhibition of β -mannosidase was observed with compounds 1 , 3 , 7 and 10 , but only weak inhibition could be detected with the alkyl- C -iminosugars on the other tested glycosidases ( α -glucosidase, α -fucosidase, α - and β -galactosidase). [ABSTRACT FROM AUTHOR]