Synthesis and antineoplastic properties of ether-linked thioglycolipids

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Abstract
Ether-linked glycero-.alpha.-and .beta.-D-glucopyranosides and glycero-1-thio-.alpha.- and .beta.-D-glucopyranosides have been synthesized by modifications of the Konigs-Knorr procedure, and their antitumor activities have been evaluated. The bioactivities of these compounds have been evaluated in five different cell lines (WEHI 3B, C653, X63/OMIL3, R6X-B15, and HL-60) and compared with the activities of 1-O-hexadecyl-2-O-methyl-sn-3-glycerophosphocholine (GPC) and its enantiomer, 3-O-hexadecyl-2-O-methyl-sn-1 GPC. The results indicate that a .alpha.-D-thioglucopyranoside [1-O-hexadecyl-2-O-methyl-3-S-(.alpha.-D-1''-thioglucopyranosyl-sn-glycerol)] is selective with respect to its action on target cells, with high activity for killing of WEHI 3B and C653 cells as determined by inhibition of [3H]thymidine incorporation into DNA and HL-60 cell cytotoxicity, but unable to induce agregation of rabbit platelets at 10-5 M. The corresponding .beta.-linked thioglycolipid was ineffective with respect to cytotoxicity against each cell line tested, indicating the importance of configuration at the anomeric position; the .beta.-thioglycoside was also ineffective with respect to inducing platelet aggregation. 1-O-Hexadecyl-2-O-methyl-sn-3-O-hexadecyl-2-O-methyl-sn-1-GPC were potent inhibitors of growth of each cell line tested but also caused rabbit platelet aggregation at concentrations .gtoreq. 10-7 M. Thus, 3-S-(.ALPHA.-thioglycopyranosyl)-sn-glycerols bearing a long-chain O-alkyl group at the sn-1 position and a methoxy group at the sn-2 position of glycerol appear to be a promosing class of antineoplastic agents with lower risk of inducing thrombosis than the widely studied platelet activating factor analogue, 1-O-octadecyl-2-O-methyl-rac-3-GPC.