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Ether-linked glycero-alpha- and beta-D-glucopyranosides and glycero-1-thio-alpha- and beta-D-glucopyranosides have been synthesized by modifications of the Königs-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 aggregation 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-GPC and 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 greater than or equal to 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 promising 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.

Both enantiomers of various etherlester glycerophosphocholines (R)and (S)-l, including platelet activating factor (PAF, 2), have been synthesized from arenesulfonate derivatives of glycidol ((R)and (S)-3) that are readily available in high enantiomeric purity. Regio-and stereospecific opening of (R)or (S)-3 with 1.0-1.4 equiv of long-chain saturated or unsaturated alcohol using boron trifluoride etherate as catalyst in CH2C12 or CHCl, solvent afforded 1(3)-0-alkyl-3(1)-0-arenesulfonyl-sn-glycerol (4) in good yields (73-83%) and with the same very high optical purity of the parent glycidyl arenesulfonate (94-99% ee). For saturated alkyl/acyl 1 and 2,O-benzylation of 4 was achieved with retention of the arenesulfonate group by using benzyl trifluoromethanesulfonate in the presence of excess 2,6-di-tert-butyl-4-methylpyridine; the C2 hydroxyl of unsaturated 0-alkyl 4 was protected as the methoxymethyl ether under mild conditions in which the arenesulfonate group is retained. Displacement of the arenesulfonate group and introduction of the phosphocholine group to produce PAF analogues complete this synthetically useful route to chiral ether-ester phospholipids with various alkyl and acyl functionalities.Ether-linked phosphoglycerides bearing a long-chain ester at C2 ((R)-1) are important structural constituents of cellular membranes of various tissues.' Since they contain the 0-alkyl linkage, alkylacyl phosphoglycerides 1 may also play important roles in cellular functions by serving as precursors of bioactive ether-linked lipids. The potent ether-linked mediator of many biochemical and physiological activities, platelet activating factor (PAF, (R)-2), can be synthesized when cells are appropriately stimulated by the sequential action of a phospholipase A2 and an acetyl-coA transferase on alkylacylglycerophosphocholine.2 R2CQ H b-I . 0 R' = C,eHa, C18H3,-A0-cis, ClgHs-Ae-CIS AlkylOCyl-PC (@l: R2 = C15H31 (+l: R2 = C,,H,, PAF (-2 R2 = CH3 (-2: R2 -CH3 (4) (a) Palameta, B.; Kates, M. (8) (a) Heymans, F.; Michel, E.; Borrel, M.-C.; Wichrowski, B.; Godfroid, J.-J.; Convert, 0.; Coeffier, E.; Tence, M.; Benveniste, J. Biochim.

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