2016年
Conformationally-locked C-glycosides: tuning aglycone interactions for optimal chaperone behaviour in Gaucher fibroblasts
ORGANIC & BIOMOLECULAR CHEMISTRY
- 巻
- 14
- 号
- 4
- 開始ページ
- 1473
- 終了ページ
- 1484
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1039/c5ob02281a
- 出版者・発行元
- ROYAL SOC CHEMISTRY
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 beta-glucosidase/beta-galactosidase and specific inhibition of human beta-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 (R).
- リンク情報
- ID情報
-
- DOI : 10.1039/c5ob02281a
- ISSN : 1477-0520
- eISSN : 1477-0539
- Web of Science ID : WOS:000369593700038