Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit ofSimplified Structures and Potent β-N-Acetylhexosaminidase Inhibition.

Xin Yan,Yuna Shimadate,Atsushi Kato,Yue-Mei Jia,Chu-Yi Yu,George W J Fleet,Yi-Xian Li

doi:10.3390/molecules25071498

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.

Highlights

Since its isolation from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 in 2009 [1], pochonicine (1) (Figure 1) has been an attractive synthetic target due to its potent and specific inhibition of β-N-acetylhexosaminidases (β-HexNAcases), including β-N-acetylglucosaminidases (β-GlcNAcases) and β-N-acetylgalactosaminidases (β-GalNAcases) [1,2]. β-HexNAcases are associated with many crucial biological processes [3]
Synthesis of acetamide modified pyrrolidines generally rely on asymmetric synthesis from
Synthesis of acetamide modified pyrrolidines generally rely on asymmetric synthesis from achiral startingof materials or begin with pyrrolidines carbohydrategenerally precursors the second strategy, Synthesis acetamide modified rely onInasymmetric synthesiscarbofrom achiral starting materials or begin with carbohydrate precursors [32]

Summary

Introduction

Since its isolation from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 in 2009 [1], pochonicine (1) (Figure 1) has been an attractive synthetic target due to its potent and specific inhibition of β-N-acetylhexosaminidases (β-HexNAcases), including β-N-acetylglucosaminidases (β-GlcNAcases) and β-N-acetylgalactosaminidases (β-GalNAcases) [1,2]. β-HexNAcases are associated with many crucial biological processes [3]. Suchlasporia TAMA 87 in 2009 [1], pochonicine (1) (Figure 1) has been an attractive synthetic target due to its potent and specific inhibition of β-N-acetylhexosaminidases (β-HexNAcases), including β-N-acetylglucosaminidases (β-GlcNAcases) and β-N-acetylgalactosaminidases (β-GalNAcases) [1,2]. Β-HexNAcases are associated with many crucial biological processes [3]. Many diseases including lysosomal storage disorders [7], type-II diabetes [6], insulin resistance [8] and Alzheimer’s disease [9,10,11] can be attributed to abnormality of β-HexNAcases. 25, 1498 β-HexNAcase inhibitors may provide alternate strategies for discovery of therof 24. Study of β-HexNAcase inhibitors may provide alternate strategies for discovery of 2therapeutic drugs.

Methods

Discussion

Conclusion