title: First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs.
abstract: The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC50 = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition.
authors.affiliation: Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. yucy@iccas.ac.cn.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Song
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kinami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Yue-Mei
authors.initials: YM
authors.lastname: Jia
authors.forename: Yi-Xian
authors.initials: YX
authors.lastname: Li
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.forename: Chu-Yi
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D050111:Imino Sugars / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D013237:Stereoisomerism; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors*
chemical_list: D001688:Biological Products; D050111:Imino Sugars; C000626197:broussonetine W; D001616:beta-Galactosidase