title: Carbonoyloxy analogs of the anti-metastatic drug swainsonine. Activation in tumor cells by esterases.
abstract: 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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: J W
authors.initials: JW
authors.lastname: Dennis
authors.forename: S L
authors.initials: SL
authors.lastname: White
authors.forename: A M
authors.initials: AM
authors.lastname: Freer
authors.forename: D
authors.initials: D
authors.lastname: Dime
mesh_terms: D000818:Animals; D001711:Biotransformation; D002240:Carbohydrate Sequence; D004950:Esterases / Q000494:pharmacology*; D008361:Mannosidases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011355:Prodrugs / Q000493:pharmacokinetics; D013047:Specific Pathogen-Free Organisms; D013329:Structure-Activity Relationship; D017026:Swainsonine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D011355:Prodrugs; D004950:Esterases; D008361:Mannosidases; D017026:Swainsonine