Cyclodextrin-based carbohydrate clusters by amide bond formation

Abstract

Per-6-amino-2,3-dimethyl-β-cyclodextrin was prepared very efficiently as its hydrochloride salt from native β-cyclodextrin in four steps and 89% overall yield. O-Acetyl-protected β-D-thioglucose and β-D-thiolactose derivatives, containing short spacer arms terminated with carboxylic acid functions, were prepared by the BF3·OEt2-catalyzed thioglycosylation of β-D-glucose pentaacetate and β-lactose octaacetate with 3-mercaptopropionic acid, respectively. Utilizing amide bond formation as the key step, these thio-β-D-glucosyl and lactosyl derivatives were coupled to per-6-amino-2,3-dimethyl-β-cyclodextrin to afford, after deprotection, perfunctionalized β-cyclodextrin-based clusters containing seven thio-β-D-glucosyl and seven β-lactosyl appendages, respectively. Molecular modeling of both these β-cyclodextrin-based clusters revealed the glucose and lactose clusters to be approximately 23 Å and 27 Å in diameter, respectively, and approximately 19 Å in height in both cases. The association constants for the complexation of the antiinflammatory drug naproxen by β-cyclodextrin, per-2,3-dimethyl-β-cyclodextrin, and the lactose cluster of β-cyclodextrin in 0.01 M phosphate buffered saline solution (pH 7.4) were found by UV-vis spectrophotometric titration to be 374 ± 75 M-1, 351 ± 70 M-1, and 165 ± 33 M-1, respectively.