Structure-activity relationship of swainsonine. Inhibition of human α-mannosidases by swainsonine analogues

Abstract

The inhibitory properties of a series of synthetic epimers and analogues of swainsonine towards the multiple forms of human alpha-mannosidases were studied in vitro and in cells in culture. Of the five epimers tested, only the 8a-epimer and 8,8a-diepimer of swainsonine were specific and competitive inhibitors (Ki values of 7.5 x 10(-5) and 2 x 10(-6) M respectively) of lysosomal alpha-mannosidases in vitro and induced storage of mannose-rich oligosaccharides in human fibroblasts in culture. The structures of these storage products indicated that processing alpha-mannosidases had also been inhibited. This was consistent with the observed inhibition in vitro of these enzymes by these compounds. In contrast, the 8-epimer, 1,8-diepimer and 2,8a-diepimer of swainsonine had no appreciable effect on any alpha-mannosidases. The corresponding open-chain analogues of swainsonine, namely 1,4-dideoxy-1,4-imino-D-mannitol, of the 8a-epimer, namely 1,4-dideoxy-1,4-imino-D-talitol, and of the 8,8a-diepimer, namely 1,4-dideoxy-1,4-imino-L-allitol, were weaker competitive inhibitors of lysosomal alpha-mannosidase, with Ki values of 1.3 x 10(-5), 1.2 x 10(-4) and 1.2 x 10(-4) M respectively. These analogues also proved less effective at inducing oligosaccharide accumulation and in disturbing glycoprotein processing. These compounds offer the opportunity to determine which alterations in the chirality of the swainsonine molecule affect its inhibitory specificity. A comparison of their biological activities has identified reagents that will be useful for studying steps in the biosynthesis and catabolism of glycoproteins and that may be of potential value in chemotherapy.

Change in specificity of glycosidase inhibition by N-alkylation of amino sugars

“…Among the factors that determine specificity are the number and chirality of the hydroxy groups, the ring structure and substitution of the ring nitrogen. Alteration of the chirality of a hydroxy group on a polyhydroxylated alkaloid generally changes the specificity of inhibition (Molyneux et al, 1986;Elbein et al, 1987;Cenci di Bello et al, 1989). Substitution of the ring nitrogen atom usually decreases the inhibitory capacity of an alkaloid (Schweden et al, 1986), but has been shown in one case to enhance inhibition (Hettkamp et al, 1984).…”

“…1,4-Dideoxy-1,4-imino-L-allitol (DIA) ( Fig. 1) is a moderately strong inhibitor of the multiple forms of human liver a-D-mannosidase (Cenci di Bello et al, 1989), but it also inhibits az-L-fucosidase, ,-D-glucosidase, ,/-N-acetylhexosaminidase and ?-D-mannosidase to a lesser extent. In the present paper the effect ofmethylation and benzylation of the pyrrolidine ring on the potency and specificity of inhibition of DIA has been investigated.…”

Glycosylation of dengue virus glycoproteins and their interactions with carbohydrate receptors: possible targets for antiviral therapy

“…The removal of terminal glucose residues may be blocked by nojirimycin or castanospermine [90], and the phosphatase-mediated conversion of the dolichylpyrophosphate released by glycosidic cleavage is inhibited by bacitracin. Brefeldin A inhibits the transport of the resultant high-mannose N-glycans to the Golgi apparatus, and further processing by mannosidase enzymes may be affected by deoxymannojirimycin or swainsonine [91,92]. Deoxynojirimycin is an inhibitor of ER a-glucosidase and disrupts the trimming of…”

Binding of sulfonium‐ion analogues of di‐epi‐swainsonine and 8‐epi‐lentiginosine to Drosophila Golgi α‐mannosidase II: The role of water in inhibitor binding

“…(+)‐Lentiginosine ( 5 ) is a powerful inhibitor of amyloglucosidases, especially glucoamylase, which are widely used in industry for the conversion of starch into glucose 13. On the other hand, 8‐ epi ‐lentiginosine ( 7 ) is a good inhibitor of lysosomal α‐mannosidase from rat epididymis (IC 50 4.6 μ M ) and of lysosomal α‐mannosidase in human lymphoblasts (IC 50 = 5.0 μ M ), although it is substantially less active than swainsonine ( 6 ) (Ki = 0.07 μ M ) on human lysosomal α‐mannosidase 14–16. Hence, a minute structural modification can lead to dramatic changes in terms of selectivity for and inhibitory activities against glycosidase enzymes.…”