title: D-Fructose-6-phosphate aldolase-catalyzed one-pot synthesis of iminocyclitols.
abstract: A one-pot chemoenzymatic method for the synthesis of a variety of new iminocyclitols from readily available, non-phosphorylated donor substrates has been developed. The method utilizes the recently discovered fructose-6-phosphate aldolase (FSA), which is functionally distinct from known aldolases in its tolerance of different donor substrates as well as acceptor substrates. Kinetic studies were performed with dihydroxyacetone (DHA), the presumed endogenous substrate for FSA, as well as hydroxy acetone (HA) and 1-hydroxy-2-butanone (HB) as donor substrates, in each case using glyceraldehyde-3-phosphate as acceptor substrate. Remarkably, FSA used the three donor substrates with equal efficiency, with kcat/KMvalues of 33, 75, and 20 M-1 s-1, respectively. This level of donor substrate tolerance is unprecedented for an aldolase. Furthermore, DHA, HA, and HB were accepted as donors in FSA-catalyzed aldol reactions with a variety of azido- and Cbz-amino aldehyde acceptors. The broad substrate tolerance of FSA and the ability to circumvent the need for phosphorylated substrates allowed for one-pot synthesis of a number of known and novel iminocyclitols in good yields, and in a very concise fashion. New iminocyclitols were assayed as inhibitors against a panel of glycosidases. Compounds 15 and 16 were specific alpha-mannosidase inhibitors, and 24 and 26 were potent and selective inhibitors of beta-N-acetylglucosaminidases in the submicromolar range. Facile access to these compounds makes them attractive core structures for further inhibitor optimization.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Zhangyong
authors.initials: Z
authors.lastname: Hong
authors.forename: Pi-Hui
authors.initials: PH
authors.lastname: Liang
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Dean
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Whalen
authors.forename: William A
authors.initials: WA
authors.lastname: Greenberg
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D002384:Catalysis; D054812:Cyclitols / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism*; D005636:Fructosephosphates / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007097:Imines / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure
chemical_list: D000447:Aldehydes; D000588:Amines; D001386:Azides; D054812:Cyclitols; D004791:Enzyme Inhibitors; D005636:Fructosephosphates; D007097:Imines; C027618:fructose-6-phosphate; D006026:Glycoside Hydrolases; D005634:Fructose-Bisphosphate Aldolase