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Inhibition of Glycosidases by Lactam Oximes: Influence of the Aglycon in Disaccharide Analogues
Author(s) -
Vonhoff Stefan,
Heightman Tom D.,
Vasella Andrea
Publication year - 1998
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(19980909)81:9<1710::aid-hlca1710>3.0.co;2-i
Subject(s) - chemistry , stereochemistry , disaccharide , lactam , glucosidases , oxime , alkyl , ic50 , substituent , enzyme , biochemistry , organic chemistry , in vitro
The influence of a substituent at the hydroximo function of the lactam analogue 1 on the inhibition of β ‐ and α ‐glucosidases is evaluated. In contrast to 1 , the O ‐alkyl oximes 5 , 6 , 9 , and 10 are selective inhibitors of β ‐glucosidases. Alkylation of the D ‐gluconohydroximo‐1,5‐lactam 19 with the triflate 12 , or condensation of the thiogluconolactam 20 with the hydroxylamines 14 or 18 afforded the benzylated cellobioside analogues 21 and 23 , respectively. The O ‐alkyl oximes 33 and 39 were prepared similarly ( Scheme 3 ). Deprotection afforded the cellobioside analogues 5 and 6 , and the O ‐alkyl oximes 9 and 10 . The lactam O ‐alkyl oximes 5 , 6 , 9 , and 10 are strong inhibitors of the β ‐glucosidase from C. saccharolyticum ( IC 50 =0.3 – 8 μ M ) and, with exception of the dodecyl analogue 9 ( IC 50 =2 μ M ), moderate‐to‐weak inhibitors of β ‐glucosidases from sweet almond ( IC 50 =60 – 1000 μ M ; see Table ). In contrast to the strong inhibition of α ‐glucosidase from brewer's yeast by 1 ( K i =2.9 μ M ), the ethers 5 , 6 , and 10 are weak inhibitors of this enzyme ( IC 50 between 2500 and >5000 μ M ). Similarly, the D ‐galactohydroximo‐1,5‐lactam 7 is a potent inhibitor of the α ‐galactosidase from coffee beans and of the β ‐galactosidases from bovine liver and E. coli ( K i =5, 10, and 0.1 μ M , resp.), while the lactoside analogue 8 is a strong inhibitor of the E. coli β ‐galactosidase ( K i =0.1 μ M ), but a moderate‐to‐weak inhibitor of coffee‐bean α ‐galactosidase and bovine‐liver β ‐galactosidase ( K i =250 μ M and IC 50 =2500 μ M , resp.). The galacto ‐configured lactam oximes 7 and 8 are good inhibitors of the β ‐glucosidase isolated from C. saccharolyticum ( K i =2.5 and 3.3 μ M , resp.).