Conformationally-locked C-glycosides: tuning aglycone interactions for optimal chaperone behaviour in Gaucher fibroblasts

  1. Navo, C.D. 1
  2. Corzana, F. 1
  3. Sánchez-Fernández, E.M. 2
  4. Busto, J.H. 1
  5. Avenoza, A. 1
  6. Zurbano, M.M. 1
  7. Nanba, E. 3
  8. Higaki, K. 3
  9. Ortiz Mellet, C. 2
  10. García Fernández, J.M. 4
  11. Peregrina, J.M. 1
  1. 1 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  2. 2 Universidad de Sevilla
    info

    Universidad de Sevilla

    Sevilla, España

    ROR https://ror.org/03yxnpp24

  3. 3 Tottori University
    info

    Tottori University

    Tottori, Japón

    ROR https://ror.org/024yc3q36

  4. 4 Instituto de Investigaciones Químicas
    info

    Instituto de Investigaciones Químicas

    Sevilla, España

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Revista:
Organic and Biomolecular Chemistry

ISSN: 1477-0520

Año de publicación: 2016

Volumen: 14

Número: 4

Páginas: 1473-1484

Tipo: Artículo

DOI: 10.1039/C5OB02281A SCOPUS: 2-s2.0-84955485276 WoS: WOS:000369593700038 GOOGLE SCHOLAR

Otras publicaciones en: Organic and Biomolecular Chemistry

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Resumen

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).