Synthesis and antineoplastic properties of ether-linked thioglycolipids.
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.
Guivisdalsky
P N
PN
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing 11367.
Bittman
R
R
Smith
Z
Z
Blank
M L
ML
Snyder
F
F
Howard
S
S
Salari
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005960:Glucosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D005995:Glyceryl Ethers / Q000138:chemical synthesis* / Q000627:therapeutic use; D006027:Glycosides / Q000138:chemical synthesis*; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005960:Glucosides; D005995:Glyceryl Ethers; D006027:Glycosides; D010742:Phospholipid Ethers