Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues.

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 ?-glucosidase (IC50 = 6.3 ?M and 0.8 ?M, respectively) and ?-galactosidase (IC50 = 2.3 ?M and 0.2 ?M, respectively); while their enantiomers, ent-3 and ent-10'-epi-3, were selective and potent inhibitors of rice ?-glucosidase (IC50 = 1.2 ?M and 1.3 ?M, respectively) and rat intestinal maltase (IC50 = 0.29 ?M and 18 ?M, 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.

SUBMITTER: Wu QK 

PROVIDER: S-EPMC6832352 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature