Biological Properties ofd- andl-1-Deoxyazasugars

• DOI: 10.1021/jm0495881
• Publication Date: 2005-03-17T05:26:48Z
• Authors: Atsushi Kato; Noriko Kato; Erika Kano; Isao Adachi; Kyoko Ikeda; Liang Yu; Tadashi Okamoto; Yasunori Banba; Hidekazu Ouchi; Hiroki Takahata; Naoki Asano
• Keywords: Iminosugar

l-Enantiomers of 1-deoxynojirimycin (DNJ), 1-deoxymannojirimycin (manno-DNJ), 1-deoxyallonojirimycin (allo-DNJ), 1-deoxyaltronojirimycin (altro-DNJ), 1-deoxygalactonojirimycin (galacto-DNJ), 1-deoxygulonojirimycin (gulo-DNJ), and 1-deoxyidonojirimycin (ido-DNJ) were prepared according to prior methods for the d-enantiomers. These enantiospecific syntheses established unambiguously absolute configuration naturally occurring DNJ, manno-DNJ, allo-DNJ, altro-DNJ, gulo-DNJ. Although d-DNJ d-galacto-DNJ are known be powerful competitive inhibitors α-glucosidase α-galactosidase, respectively, with Ki values in nM range, l-DNJ l-galacto-DNJ noncompetitive μM range. However, azasugar mimicking structure terminal sugar moiety natural substrate is not always an inhibitor glycosidase responsible hydrolysis. d-manno-DNJ as a much better α-l-fucosidase than α-mannosidase, while l-allo-DNJ was α-mannosidase. can regarded 6-hydroxylated derivative deoxyfuconojirimycin (DFJ), which value this replacement methyl group DFJ by hydroxymethyl reduced its affinity about 50-fold. This suggests that there hydrophobic region or around active site α-l-fucosidase. It has been found human lysosomal glycosidases have therapeutic potential corresponding storage diseases (Nat. Med. 1999, 5, 112; Proc. Natl. Acad. Sci. USA, 2002, 99, 15428). Inhibition 1-deoxyazasugars synthesized investigated. potent α-galactosidase (IC50 = 90 nM) now being evaluated preclinically use Fabry disease, inhibiting 40 potently does appear become agent because additional inhibitory activity toward glycoprotein processing α-glucosidases. On other hand, although moderate α-mannosidase 64 μM), it may key compound drug design agents α-mannosidosis.