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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.

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The biological activity of 14 analogues of sparsomycin (1) was studied in cell-free systems of Escherichia coli, Saccharomyces cerevisiae, and Sulfolobus solfataricus by measuring the inhibition of protein synthesis. The inhibition of L1210 colony formation in soft agar and bacterial cell growth in solid as well as in liquid medium was also examined. Each analogue possesses not more than two structural modifications of the sparsomycin molecule. This enabled us to determine unambiguously several structural and stereochemical features that are required for an optimal biological activity in these assays. Sparsomycin, having the SCRS chirality, is the most potent of the four possible stereoisomers. The results obtained with compounds 5-7 indicate that the presence of an oxygen atom on the S (alpha) atom is essential. Substitution of the bivalent sulfur atom by a CH2 group (10) or of the SCH3 moiety by a Cl atom (12) affects the activity of the molecule partially. Compound 12 is surprisingly active against intact cells. Substitution of the C(6)-CH3 group by a H(14) reduces the activity of the molecule. Isomerization of the trans double bond into the cis double bond yields cis-sparsomycin (15), which is inactive. The hydrophobic derivatives 8, 9, and 11 are considerably more active than sparsomycin; thus the ribosomal binding site for sparsomycin may have a hydrophobic character.

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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.