Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease
We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α...
| Những tác giả chính: | , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
| Được phát hành: |
Royal Society of Chemistry
2016
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| _version_ | 1826290006869671936 |
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| author | Kato, A Nakagome, I Sato, K Yamamoto, A Adachi, I Nash, R Fleet, G Natori, Y Watanabe, Y Imahori, T Yoshimura, Y Takahata, H Hirono, S |
| author_facet | Kato, A Nakagome, I Sato, K Yamamoto, A Adachi, I Nash, R Fleet, G Natori, Y Watanabe, Y Imahori, T Yoshimura, Y Takahata, H Hirono, S |
| author_sort | Kato, A |
| collection | OXFORD |
| description | We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease. |
| first_indexed | 2024-03-07T02:37:35Z |
| format | Journal article |
| id | oxford-uuid:a950c25a-e5fb-4dd9-b529-48b90c9fd73b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:37:35Z |
| publishDate | 2016 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:a950c25a-e5fb-4dd9-b529-48b90c9fd73b2022-03-27T03:07:46ZDocking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a950c25a-e5fb-4dd9-b529-48b90c9fd73bEnglishSymplectic Elements at OxfordRoyal Society of Chemistry2016Kato, ANakagome, ISato, KYamamoto, AAdachi, INash, RFleet, GNatori, YWatanabe, YImahori, TYoshimura, YTakahata, HHirono, SWe report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease. |
| spellingShingle | Kato, A Nakagome, I Sato, K Yamamoto, A Adachi, I Nash, R Fleet, G Natori, Y Watanabe, Y Imahori, T Yoshimura, Y Takahata, H Hirono, S Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title | Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title_full | Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title_fullStr | Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title_full_unstemmed | Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title_short | Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease |
| title_sort | docking study and biological evaluation of pyrrolidine based iminosugars as pharmacological chaperones for gaucher disease |
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