Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues.

Wu Wu,Fleet Fleet,Jia Jia,Yu Yu,Kato Kato,Kinami Kinami,Li Li

doi:10.3390/molecules24203712

Abstract

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%–31% overall yield. The natural product broussonetine M (3) and 10’-epi-3 were potent inhibitors of β-glucosidase (IC50 = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC50 = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent-3 and ent-10’-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC50 = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10’ hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.

Highlights

In the past several decades, numerous polyhydroxylated pyrrolidine iminosugars have been isolated and synthesized, which has enriched the extended family of iminosugars [1,2,3,4,5,6,7]; these natural products, together with their synthetic analogues, have exhibited a variety of important biological activities and shown great potential as chemotherapeutic agents for an ever widening number of diseases [6,8]
Though the first synthesis of broussonetine M (3) was accomplished with d-serine as the starting material [47], we have shown that most broussonetines can be efficiently constructed via a general synthetic strategy employing sugar-derived cyclic nitrones [39,40]
Only the stereocenter in alcohol 15 is constructed by virtue of an asymmetric reaction; of the four stereocenters on the pyrrolidine ring, three were determined by sugar-derived cyclic starting nitrone 14 and the fourth was formed by the high diastereoselectivity of organometallic addition to the nitrone 14

Summary

Introduction

In the past several decades, numerous polyhydroxylated pyrrolidine iminosugars have been isolated and synthesized, which has enriched the extended family of iminosugars [1,2,3,4,5,6,7]; these natural products, together with their synthetic analogues, have exhibited a variety of important biological activities and shown great potential as chemotherapeutic agents for an ever widening number of diseases [6,8]. DAB (1,4-dideoxy-1,4-imino-d-arabinitol, 1) [9] and DMDP (2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine, 2) [10] are among the most widespread and studied iminosugars (Figure 1). DAB (1), isolated in 1985, is a powerful α-glucosidase inhibitor [11,12,13,14,15], whereas DMDP (2) is a potent inhibitor of bovine liver β-glucosidase and β-galactosidase (IC50 = 9.7 μM and 3.3 μM, respectively) [16]. DAB (1) was found to be a potent inhibitor of glycogen phosphorylase, which made it a potential therapeutic agent for the treatment of diabetes [17]. (ent-1) [15] and l-DMDP (ent-2) are both potent and specific α-glucosidase inhibitors [16,18].

Methods

Results

Conclusion