The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose.
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 nitro...
| Auteurs principaux: | , , , , , , |
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| Format: | Journal article |
| Langue: | English |
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1993
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| _version_ | 1826298762196156416 |
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| author | Winchester, B al Daher, S Carpenter, N Cenci di Bello, I Choi, S Fairbanks, A Fleet, G |
| author_facet | Winchester, B al Daher, S Carpenter, N Cenci di Bello, I Choi, S Fairbanks, A Fleet, G |
| author_sort | Winchester, B |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:51:45Z |
| format | Journal article |
| id | oxford-uuid:d533e1cd-bdf7-47ec-927c-e52f4635030a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:51:45Z |
| publishDate | 1993 |
| record_format | dspace |
| spelling | oxford-uuid:d533e1cd-bdf7-47ec-927c-e52f4635030a2022-03-27T08:24:15ZThe structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d533e1cd-bdf7-47ec-927c-e52f4635030aEnglishSymplectic Elements at Oxford1993Winchester, Bal Daher, SCarpenter, NCenci di Bello, IChoi, SFairbanks, AFleet, GEight 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. |
| spellingShingle | Winchester, B al Daher, S Carpenter, N Cenci di Bello, I Choi, S Fairbanks, A Fleet, G The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title | The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title_full | The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title_fullStr | The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title_full_unstemmed | The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title_short | The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose. |
| title_sort | structural basis of the inhibition of human alpha mannosidases by azafuranose analogues of mannose |
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