Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of optical isomers of ether and thioether lipids.
Four 1-beta-D-arabinofuranosylcytosine conjugates (ara-C) (1a, b and 2a, b) of sn-1 and sn-3 isomers of 1-O-octadecyl-2-O-palmitoylglycerol and its 1-S-alkyl analogue have been synthesized, and their antitumor activity against L1210 lymphoid leukemia in mice were compared with those of the previous conjugates (3a, b) of racemates in order to determine the significance of chirality of the glycerol moieties for activity. Administration (i.p.) of a single dose (300 mg/kg) of conjugates of sn-1 (1a), sn-3 (2a) and rac (3a) isomers of the ether lipid increased lifespan of i.p. implanted L1210 lymphoid leukemic DBA/2J mice by 169, 175 and 236%, respectively. The sn-1 (1b), sn-3 (2b), and rac (3b) isomers of the thioether lipid with a single dose of 300 mg/kg produced an increase in lifespan values of 238, 263 and 250%, respectively. The results indicate that chirality of the glycerol moieties appears not to be critical for the activity, and racemates 3a and 3b are promising prodrugs of ara-C for further clinical investigations.
Hong
C I
CI
Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263.
An
S H
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Nechaev
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Kirisits
A J
AJ
Vig
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West
C R
CR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry; D004987:Ethers / Q000627:therapeutic use*; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D007939:Leukemia L1210 / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D010742:Phospholipid Ethers / Q000737:chemistry*; D013237:Stereoisomerism; D013440:Sulfides / Q000627:therapeutic use*; D016019:Survival Analysis
D000970:Antineoplastic Agents; D004987:Ethers; D010742:Phospholipid Ethers; D013440:Sulfides; D003561:Cytarabine; C085204:ara-CDP-1-O-octadecyl-2-O-palmitoyl-sn-glycerol; C063784:ara-CDP-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol; C009465:thioglycerol; D005990:Glycerol