Piperidine Azasugars Displaying Competitive alpha-Rhamnosidase Inhibition and their Kinetic Mechanism

Abstract

Azasugars derived from L-alanine and L-serine were screened for inhibitory activity against alpha-rhamnosidase. The enantiomers of 1,6-dideoxynojirimycin (ent-1,6-dDNJ) (1) and (2S,3R)-2-(hydroxymethyl)piperidin-3-ol (5) showed highly specific and potent inhibition against alpha-rhamnosidase with K-i values of 4.2 and 16.6 mu M, respectively. Structure of the best inhibitor features the same stereochemical configuration as L-rhamnose at C2, C3, and C4 centers. In kinetic studies, both compounds exhibited competitive inhibition behavior. Compound 1 manifested simple reversible slow-binding inhibition with the following kinetic parameters: k(3)= 1.17 nM(-1) min(-1), k(4)=5.96 x10(-3) min(-1), and K-i(app)=5.1 mM.