Swainsonine (SW), a
plant alkaloid and inhibitor of alpha-
mannosidases, has been shown to inhibit N-linked
oligosaccharide processing and to block
tumor cell
metastasis in mice. In this study, a series of SW analogs were chemically synthesized and compared for inhibition of complex-type N-linked
oligosaccharide processing in cultured MDAY-D2
tumor cells, for inhibition of alpha-
mannosidases in vitro, and for stimulation of bone marrow proliferation in vivo. Carbonoyloxy substitutions at the 2 and 8 carbons of SW reduced inhibitor activity by 2-3 orders of magnitude for Jack Bean and MDAY-D2
tumor cell lysosomal alpha-
mannosidases in vitro. However, 2-p-nitrobenzoyloxy-, 2-octanoyloxy- and 2-butanoyloxy-derivatives of SW retained full activity as inhibitors of Golgi
oligosaccharide processing in viable MDAY-D2
tumor cells. Inhibition of
oligosaccharide processing was reduced by the
esterase inhibitor
diethyl p-nitrophenyl phosphate, suggesting that although 2-p-nitrobenzoyloxy-SW, 2-octanoyloxy-SW and 2-butanoyloxy-SW are relatively poor inhibitors of alpha-
mannosidases in vitro, the compounds enter cells at a rate comparable to that of SW, and are converted to SW by cellular
esterases. The more lipophilic
esters, 2-benzoyloxy-SW, 2-toluoyloxy-SW, 8-palmitoyloxy-SW and 8-myristinoyloxy-SW, showed IC50 values at least 10 times higher for inhibition of Golgi
oligosaccharide processing, probably due to less efficient entry of the compounds into
tumor cells. The anti-metastatic activities of SW and two analogs were tested and shown to correlate with the IC50 values for inhibition of Golgi
oligosaccharide processing in cultured tumor cells. In vivo, SW and the analogs were administered intraperitoneally to mice and found to have comparable activities as stimulators of bone marrow cell proliferation. Carbonoyloxy substitutions at the 2- or 8-position of SW with other chemical groups may lead to new drugs with improved pharmacokinetics and anti-
cancer activity.