Abstract. The synthesis of a series of six less-lipophilic analogues of the a-glucosidase inhibitor N-decyl-I-deoxynojirimycin (N-decyl-dNM, 5) is described. With the incorporation of a single oxygen atom, particularly at position seven in the N-decyl side-chain to give N-(7-oxadecyl)-dNM (8), the therapeutic ratio (a-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. Compound 8 inhibits purified porcine liver a-glucosidase I with an IC,, value of 0.28 p M . The position of the oxygen atom in the N-decyl side-chain is of importance since N-(3-oxadecyl)-dNM (7) is less active than 8 and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of eight ester derivatives of N-(7-oxadecyl)-dNM is described. All of these ester analogues are less active a-glucosidase inhibitors than the parent compound 8 in HepG2 cells. The compounds were further analyzed for antiviral and immunomodulatory activity in uitro. I t is found that the most potent a-glucosidase I inhibitor from this study N-(7-oxadecyl)-dNM (8) inhibits HIV-1 -induced syncytia formation and lymphocyte proliferation in uitro. Finally, compound 8 was investigated in uiuo. N-(7-Oxadecyl)-dNM (8) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.

The synthesis of a series of analogues of the a-glucosidase inhibitor 1-deoxynojirimycin (dNM, 1) and of the a-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 a ,-antitrypsin in human hepatoma HepG2 cells and with the syncytium-inducing capacity of HIV-infected cells was investigated. A strong correlation was observed between a-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-6-0-butyryl-dNM (42) and N-decyl-6-0-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: 3-0-methyl-dNM (49) and 3-0-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-0-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.i' Present address: h Nomenclature and abbreviations: AIDS = Acquired immune&ficiency syndrome, Bn = benzyl, CAS = castanospermine (2), CI,. T M B = chlorine-3,3',S,S'-tetramethylbenzidine, d N M = 1deoxynojirimycin = 1,s-dideoxy-1 ,S-imino-D-glucitol (I), dMM = 1deoxymannojirimycin = 1,5-dideoxy-l,S-imino-D-mannitol (3), HIV = human immunodeficiency virus, HM = high mannose, 2.6-lutidine = 2,6.dimethylpyridine, SDS-PAGE = Sodium-dodecyl-sulphate poly.acrylamide-gel-electro~horesis, sw = swainsonine (4, triflate = trifluoromethane sulphonate.

1993 organic chemistry, review organic chemistry, review Z 0200 31 -303 Chemical Modification of Azasugars, Inhibitors of N-Glycoprotein-Processing Glycosidases and of HIV-I Infection. Review and Structure-Activity Relationships -(113 refs.) -(VAN DEN BROEK, L. A. G. M.; VERMAAS, D. J.; HESKAMP, B. M.; VAN BOECKEL, C. A. A.; TAN, M. C. A. A.; BOLSCHER, J. G. M.; PLOEGH, H. L.; VAN KEMENADE, F. J.; DE GOEDE, R. E. Y.; MIEDEMA, F.; Recl. Trav. Chim. Pays-Bas 112 (1993) 2, 82-94; Dep. Med. Chem. III, Organon Int. BV, 5340 BH Oss, Neth.; EN)