Synthesis of oxygen‐substituted N‐alkyl 1‐deoxynojirimycin derivatives: Aza sugar α‐glucosidase inhibitors showing antiviral (HIV‐1) and immunosuppressive activity

Abstract

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.

Improved cellular inhibitors for glycoprotein processing α-glucosidases: biological characterisation of alkyl- and arylalkyl-N-substituted deoxynojirimycins

“…16 The therapeutic potential of imino sugars has never been fully realised mainly due to the inability to gain access to the ER. 11,12,17 The FOS assay provides a robust technique for examining a-glucosidase inhibition in the ER and provides an analytical snapshot of the inhibitory potential of compounds in a cellular context. The inhibitory activity of compounds was assessed at one concentration, which makes a comparison of efficacy simplified.…”

Chemistry and Structure-Activity Relationships of Glucosidase Inhibitors

“…More detailed studies have shown that the ICso values of 1-deoxynojirimycin for intestinal a-glucosidases of various origins (mouse, rat, dog, monkey) are in the range of 6.6-16 x 1O-x M for sucrase and 7.4-63 x 10-8 M for maltase (MURAO and MIYATA 1980;YOSHIKUNI 1988YOSHIKUNI , 1991. (78) is an excellent starting material for chemical derivatization and can be selectively substituted at the nitrogen atom either by treatment with reactive alkyl halides (path A) or by reductive alkylation with carbonyl compounds (path B), without using protecting groups (JUNGE et al 1979;MATSUMURA et al 1979a,b;MURAI et al 1979;JUNGE et al 1981; VAN DEN BROEK et al 1994). Further preparative methods were developed for the N-hydroxyethyl derivative 97 (BA Y m 1099, miglitol) (KINAST et al 1982;KÖBERNICK 1981;HINSKEN 1990).…”

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

“…Van den Broek et al have shown that the introduction of an ether function into the Nalkyl chain decreases the cytotoxicity (26 compared to 30 in Table 1). [198] The N-5-(adamantan-1yl-methoxy)-pentyl (AMP) functionalized 1-deoxynojirmycin 6 proved to be a very potent GCS inhibitor. [199] Translocation of the AMP moiety to other positions of 1-deoxynojirmycin abolished its ability to inhibit GCS, with the exception of b-aza-C-glycoside derivatives 33 and 34.…”