title: The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose.
abstract: Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.
authors.affiliation: Division of Biochemistry and Metabolism, Institute of Child Health University of London, U.K.
authors.forename: B
authors.initials: B
authors.lastname: Winchester
authors.forename: S
authors.initials: S
authors.lastname: al Daher
authors.forename: N C
authors.initials: NC
authors.lastname: Carpenter
authors.forename: I
authors.initials: I
authors.lastname: Cenci di Bello
authors.forename: S S
authors.initials: SS
authors.lastname: Choi
authors.forename: A J
authors.initials: AJ
authors.lastname: Fairbanks
authors.forename: G W
authors.initials: GW
authors.lastname: Fleet
mesh_terms: D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D006868:Hydrolysis; D050113:Imino Furanoses; D008099:Liver / Q000201:enzymology*; D008247:Lysosomes / Q000201:enzymology; D008353:Mannitol / Q000031:analogs & derivatives; D008358:Mannose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011134:Polysaccharides / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017026:Swainsonine / Q000494:pharmacology; D043323:alpha-Mannosidase
chemical_list: D050113:Imino Furanoses; D011134:Polysaccharides; D011759:Pyrrolidines; D008353:Mannitol; C047214:1,4-dideoxy-1,4-iminomannitol; D008361:Mannosidases; D043323:alpha-Mannosidase; D008358:Mannose; D017026:Swainsonine