PMID: 8457203Mar 15, 1993Paper

The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose

The Biochemical Journal
B WinchesterG W Fleet

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 inhi...Continue Reading

Citations

Apr 15, 2016·Pharmacognosy Magazine·Shaza Mohamed Al-MassaraniHoong-Kun Fun
May 7, 2016·Carbohydrate Research·Monika PolákováIvana Holková
Jun 17, 2005·Organic Letters·Laurent ChabaudPhilippe Renaud
Jun 2, 2007·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·María de los Angeles MonclusMiguel Walter Fornés
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