2024-03-29T11:31:52Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1288062016-12-01T08:19:30Zcom_10261_38com_10261_5col_10261_291
DIGITAL.CSIC
author
Navo, C.D.
author
Corzana, Francisco
author
Sánchez-Fernández, Elena M.
author
Busto, J.H.
author
Avenoza, A.
author
Namba, E.
author
Higaki, Katsumi
author
Ortiz-Mellet, Carmen
author
García-Fernández, José Manuel
author
Peregrina, J.M.
2016-02-08T08:19:08Z
2016-02-08T08:19:08Z
2016
Organic and Biomolecular Chemistry, 14(4): 1474-1484 (2016)
http://hdl.handle.net/10261/128806
10.1039/C5OB02281A
A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver β-glucosidase/β-galactosidase and specific inhibition of human β-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol®
eng
openAccess
Conformationally-Locked C-Glycosides: Tuning Aglycone Interactions for Optimal Cheperone Behaviour in Gaucher Fibroblasts
artículo
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URL
https://digital.csic.es/bitstream/10261/128806/1/OBC_APP%20derivatives_JMGF_2.docx
File
MD5
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application/vnd.openxmlformats-officedocument.wordprocessingml.document
OBC_APP derivatives_JMGF_2.docx