Chemical modification of azasugars, inhibitors of N-glycoprotein-processing glycosidases and of HIV-I infection: Review and structure-activity relationships
In: Recueil des Travaux Chimiques des Pays-Bas, Jg. 112 (2010-09-02), S. 82-94
Online
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Zugriff:
The synthesis of a series of analogues of the α-glucosidase inhibitor 1-deoxynojirimycin (dNM, 1) and of the α-mannosidase inhibitor 1-deoxymannojirimycin (dMM, 3) is described. The ability of dNM, dMM and a series of N-alkylated dNM and dMM derivatives to interfere with biosynthesis, transport and maturation of the glycoprotein α1-antitrypsin in human hepatoma HepG2 cells and with the syncytium-inducing capacity of HIV-infected cells was investigated. A strong correlation was observed between α-glucosidase inhibition found in HepG2 cells and antiviral activity in HIV-I-infected cells. N-Butyl- (35), N-pentyl- (38), N-benzyl- (41) and N-decyl-dNM (47) showed high activity in both assays. N-Decyl-dNM was active at 0.01 mM but showed drug-related cell toxicity at concentrations exceeding 0.1 mM. Branching of the N-alkyl side chain reduced the activity of dNM derivatives considerably. N-Benzyl-6-O-butyryl-dNM (42) and N-decyl-6-O-benzoyl-dNM (48) showed activity comparable to that of N-benzyl-dNM (41) and N-decyl-dNM (47), respectively. None of the dMM analogues prevented HIV-induced syncytia formation. The 3-hydroxyl group in dNM and in dMM plays a crucial role in the interaction of these drugs with the corresponding processing glycosidases: 3-O-methyl-dNM (49) and 3-O-methyl-dMM (56) were inactive in both assays. The plasma membrane constitutes a permeability barrier for castanospermine (CAS, 2), but not for dNM, since the activity of CAS in streptolysin-O-permeabilized HepG2 cells was significantly higher than that in intact HepG2 cells. Finally, an overview is given of structures, other than the many N-substituted derivatives that were described, related to dNM and dMM that have appeared in the literature in recent years.
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Chemical modification of azasugars, inhibitors of N-glycoprotein-processing glycosidases and of HIV-I infection: Review and structure-activity relationships
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Autor/in / Beteiligte Person: | R. E. Y. de Goede ; Heskamp, B. M. ; Bolscher, J. G. M. ; Miedema, Frank ; C. A. A. Van Boeckel ; Vermaas, D. J. ; F. J. van Kemenade ; L. A. G. M. Van Den Broek ; Tan, M. C. A. A. ; Ploegh, Hidde L. |
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Zeitschrift: | Recueil des Travaux Chimiques des Pays-Bas, Jg. 112 (2010-09-02), S. 82-94 |
Veröffentlichung: | Wiley, 2010 |
Medientyp: | unknown |
ISSN: | 0165-0513 (print) |
DOI: | 10.1002/recl.19931120204 |
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