Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit ofSimplified Structures and Potent β-<i>N</i>-Acetylhexosaminidase Inhibition

Abstract

Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.

Keywords

• pochonicine
• pharmacophore
• synthesis
• β-<i>n</i>-acetylhexosaminidase
• iminosugars
• structure-activity relationship