CARBONOYLOXY ANALOGS OF THE ANTIMETASTATIC DRUG SWAINSONINE - ACTIVATION IN TUMOR-CELLS BY ESTERASES

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 an alogs were chemically synthesized and compared for inhibition of compl ex-type N-linked oligosaccharide processing in cultured MDAY-D2 tumor cells, for inhibition of alpha-mannosidases in vitro, and for stimulat ion of bone marrow proliferation in vivo. Carbonoyloxy substitutions a t the 2 and 8 carbons of SW reduced inhibitor activity by 2-3 orders o f magnitude for Jack Bean and MDAY-D2 tumor cell lysosomal alpha-manno sidases 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. Inhibi tion of oligosaccharide processing was reduced by the esterase inhibit or diethyl p-nitrophenyl phosphate, suggesting that although 2-p-nitro benzoyloxy-SW, 2-octanoyloxy-SW and 2-butanoyloxy-SW are relatively po or inhibitors of alpha-mannosidases in vitro, the compounds enter cell s at a rate comparable to that of SW, and are converted to SW by cellu lar esterases. The more lipophilic esters, 2-benzoyloxy-SW, 2-toluoylo xy-SW, 8-palmitoyloxy-SW and 8-myristinoyloxy-SW, showed IC50 values a t least 10 times higher for inhibition of Golgi oligosaccharide proces sing, probably due to less efficient entry of the compounds into tumor cells. The anti-metastatic activities of SW and two analogs were test ed and shown to correlate with the IC50 values for inhibition of Golgi oligosaccharide processing in cultured tumor cells. In vivo, SW and t he analogs were administered intraperitoneally to mice and found to ha ve comparable activities as stimulators of bone marrow cell proliferat ion. Carbonoyloxy substitutions at the 2- or 8-position of SW with oth er chemical groups may lead to new drugs with improved pharmacokinetic s and anti-cancer activity.