Syntheses of racemic and nearly optically pure ether lipids and evaluation of in vitro antineoplastic activities.
In addition to rac-2-O-methyl-1-O-octadecylglycero-3-phosphocholine (rac-ET-18-OCH3, rac-Edelfosine, 1), three racemic ether lipid analogs, 4, 5, and 6, were synthesized where N,N-dimethylamino, N-methylpyrrolidino, and N-methylmorpholino groups, respectively, have been substituted for the trimethylammonio group. The two enantiomers, (R)-ET-18-OCH3 (2) and (S)-ET-18-OCH3 (3), and all four possible chiral methylcholine analogs, 7, 8, 9, and 10, of (R)-ET-18-OCH3 (2) were also synthesized. Three human leukemic cell lines (CEM, HUT 78, and Namalwa) were used to assess the in vitro antineoplastic properties of these 10 ether lipid analogs. At ether lipid concentrations of 5-50 micrograms/mL, dose- and time-dependent cytotoxicities were demonstrated up to 24 h. CEM and HUT 78, both T cell derived, were more sensitive to the ether lipids than Namalwa, which is B cell derived. rac-ET-18-OCH3 (1) with its R and S enantiomeric forms, 2 and 3, respectively, exhibited modest stereoselectivity in HUT 78 and Namalwa with 1 and 2 slightly more cytotoxic than 3. Ether lipid (EL) analogs 4, 5, and 6 demonstrated significantly greater cytotoxicity in normal peripheral lymphocytes, 4 and 6 exhibited a modest increase in cytotoxicity in HUT 78 and Namalwa (P < 0.05), and 5 demonstrated greater cytotoxicity (P < 0.05) in Namalwa than the parent EL 1. The calculated 24 h ID50 values suggest that the beta-methyl analogs, 9 and 10, were more cytotoxic than the alpha-methyl analogs, 7 and 8, in all the tested cancer cell lines.
Duclos
R I
RI
School of Pharmacy, University of Connecticut, Storrs 06269-2092.
Chia
H H
HH
Abdelmageed
O H
OH
Esber
H
H
Fournier
D J
DJ
Makriyannis
A
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010742:Phospholipid Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010742:Phospholipid Ethers; C026659:edelfosine