Synthesis and glycosidase inhibition of broussonetine M and its analogues

Journal article

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.

Authors: Wu, Q; Kinami, K; Kato, A; Li, Y; Fleet, G

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Molecules
• Volume: 24
• Issue: 20
• Article number: 3712
• Publication date: 2019-10-15
• Acceptance date: 2019-10-14
• DOI: 10.3390/molecules24203712
• EISSN: 1420-3049
• ISSN: 1420-3049
• Language: English
• Keywords: FFR