Chemical modification of azasugars, inhibitors of N‐glycoprotein‐processing glycosidases and of HIV‐I infection: Review and structure‐activity relationships

Abstract

Abstract 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 α 1 ‐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.