2006
DOI: 10.1039/b518117h
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Nucleophilic opening of epoxyazepanes: expanding the family of polyhydroxyazepane-based glycosidase inhibitors

Abstract: A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species and subsequent hydrogenolysis. One tetrahydroxylated azepane, a ring homologue of deoxymannojirimycin, displays a selective and fairly good inhibition of alpha-L-fucosidase.

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Cited by 34 publications
(14 citation statements)
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“…This change in the inhibitory activity by N-benzylation may indicate that -Lfucosidases have a lipophilic pocket near the active site which makes hydrophobic interactions with the enzyme more important than the stereochemistry of the hydroxyl groups of the inhibitor. Furthermore, compound 179 [59], a D-manno configured azepane and the exact homologue of deoxymannojirimycin, does not inhibit the corresponding mannosidase but displayes a competitive inhibition towards bovine kidney -L-fucosidase (K i = 10 μM). This fact reinforces the low influence of the stereochemistry of the hydroxyl groups in azepane-type inhibitors.…”
Section: Polyhydroxyazepanesmentioning
confidence: 98%
“…This change in the inhibitory activity by N-benzylation may indicate that -Lfucosidases have a lipophilic pocket near the active site which makes hydrophobic interactions with the enzyme more important than the stereochemistry of the hydroxyl groups of the inhibitor. Furthermore, compound 179 [59], a D-manno configured azepane and the exact homologue of deoxymannojirimycin, does not inhibit the corresponding mannosidase but displayes a competitive inhibition towards bovine kidney -L-fucosidase (K i = 10 μM). This fact reinforces the low influence of the stereochemistry of the hydroxyl groups in azepane-type inhibitors.…”
Section: Polyhydroxyazepanesmentioning
confidence: 98%
“…Formation of a cyclic sulfate from diol 4a, either in a one-step reaction using SO 2 Cl 2 or in a two-step procedure via the formation of a cyclic sulfite was not successful. Treatment of the unsaturated azepane 2 with m-CPBA in dichloromethane, as previously described for similar compounds [26], afforded a mixture of epoxides 12a,b in low yield (<30%), whatever the conditions tested (equivalents of m-CPBA from 1.5 to 5.6, reaction time from 4 to 48 h, temperature from 0°C to 40°C). Finally, preparation of epoxides from unsaturated azepanes 2 and 3 was best carried out using dimethyldioxirane by reaction with Oxone Ò in acetone in the presence of an excess of sodium hydrogenocarbonate as described in the glycal series [27].…”
Section: Resultsmentioning
confidence: 99%
“…[28], which afforded epoxides 12a,b and 13a,b in 78% and 84% yield respectively from 2 and 3. Surprisingly, the direct ring opening of oxiranes 12 or 13 under acid or base catalysis proved quite unsuccessful [26], thus a recent procedure using acetic anhydride as solvent in the presence of a catalytic amount of erbium triflate was used [29]. When applied to epoxide 12, the reaction proceeded smoothly to give transdiacetates 14a,14b in good yield (87%) as a mixture of separable diastereomers (70:30).…”
Section: Resultsmentioning
confidence: 99%
“…Recently, the great concern in the chemistry, biochemistry, and pharmacology of glycosidase inhibitors has lead to many types of natural and synthetic glycosidase inhibitors (Asano et al, 2000;Asano, 2003;Berecibar et al, 1999;Kim et al, 2006;Li et al, 2006;Pandey et al, 2006). Synthetic enantiomers of natural iminosugars are frequently powerful glycosidase inhibitors (d'Alonzo et al, 2009;Macchi et al, 2010).…”
Section: Introductionmentioning
confidence: 99%
“…Previously reported glycosidase inhibitors were sugar mimics (azasugars and carbasugars) and their analogs; however, no efforts were made to discover new scaffolds of better pharmacokinetic profiles, chemical stabilities, and higher potencies (Wang et al, 2013;Kooij et al, 2013;Asano et al, 2000;Asano, 2003;Berecibar et al, 1999;Kim et al, 2006;Li et al, 2006;Pandey et al, 2006).…”
Section: Introductionmentioning
confidence: 99%