title: C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat.
abstract: The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Jenkinson
authors.forename: Daniel
authors.initials: D
authors.lastname: Best
authors.forename: A Waldo
authors.initials: AW
authors.lastname: Saville
authors.forename: James
authors.initials: J
authors.lastname: Mui
authors.forename: R Fernando
authors.initials: RF
authors.lastname: Martínez
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Takahito
authors.initials: T
authors.lastname: Kunimatsu
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Alonzi
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Frederic
authors.initials: F
authors.lastname: Becq
authors.forename: Yves
authors.initials: Y
authors.lastname: Blériot
authors.forename: Francis X
authors.initials: FX
authors.lastname: Wilson
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Weymouth-Wilson
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001688:Biological Products; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars; C045621:miglitol; D017485:1-Deoxynojirimycin; C059896:miglustat; D000520:alpha-Glucosidases