SYNTHESES OF RACEMIC AND NEARLY OPTICALLY PURE ETHER LIPIDS AND EVALUATION OF IN-VITRO ANTINEOPLASTIC ACTIVITIES

In addition to c-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-methylpyrrolidi no, 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 t o assess the in vitro antineoplastic properties of these 10 ether lipi d analogs. At ether lipid concentrations of 5-50 mu g/mL, dose- and ti me-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 stereosele ctivity in HUT 78 and Namalwa with 1 and 2 slightly more cytotoxic tha n 3. Ether lipid (EL) analogs 4, 5, and 6 demonstrated significantly g reater cytotoxicity in normal peripheral lymphocytes, 4 and 6 exhibite d 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-me thyl analogs, 9 and 10, were more cytotoxic than the alpha-methyl anal ogs, 7 and 8, in all the tested cancer cell lines.