Bittman R, Byun H S, Mercier B, Salari H
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing 11367.
J Med Chem. 1994 Feb 4;37(3):425-30. doi: 10.1021/jm00029a016.
The enantiomers of two isosteric phosphonate analogs of the ether-linked antitumor agent 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OMe) were synthesized and evaluated for their cytotoxicity against various mouse leukemic cell lines in vitro and in vivo. The key step in the synthesis of the alkyloxy and alkylthio analogs (1 and 2, respectively) is the opening of an epoxide [hexadecyl 2-oxiranylmethyl ether (4) or hexadecyl 2-oxiranylmethyl thioether (8)] by LiCH2P(O)(OMe)2 using BF3.Et2O in tetrahydrofuran at low temperature. The cytotoxic activities of the hexadecyloxy and hexadecylthio phosphonate analogs of ET-18-OMe (1 and 2) against the murine leukemias WEHI-3B,L1210, and P388 were similar, indicating that substitution of a sulfur atom for oxygen in the long-chain ether does not result in a significant difference in cytotoxicity. The IC50 values of 1 and 2 were in the range of 1-5 microM. Alkyloxy phosphonate 1 was highly effective in inhibiting the growth of WEHI-3B and P388 tumors implanted in BALB/C mice. The alkyloxy and alkylthio phosphonates 1 and 2 prolonged the survival of CD1 mice bearing L1210 tumors. The antitumor activities of the phosphonate analogs of ET-18-OMe in these in vitro and in vivo studies were independent of chirality, consistent with previous studies with the enantiomers of 1-O-hexadecyl-2-O-methyl-sn-glycero-3-phosphocholine.
合成了醚键连接的抗肿瘤药物1-O-十八烷基-2-O-甲基-sn-甘油-3-磷酸胆碱（ET-18-OMe）的两种等排膦酸酯类似物的对映体，并在体外和体内评估了它们对各种小鼠白血病细胞系的细胞毒性。烷氧基和烷硫基类似物（分别为1和2）合成中的关键步骤是在低温下于四氢呋喃中，使用BF3·Et2O，通过LiCH2P(O)(OMe)2使环氧化物[十六烷基2-环氧乙烷基甲基醚（4）或十六烷基2-环氧乙烷基甲基硫醚（8）]开环。ET-18-OMe的十六烷氧基和十六烷硫基膦酸酯类似物（1和2）对小鼠白血病WEHI-3B、L1210和P388的细胞毒性活性相似，表明在长链醚中用硫原子取代氧原子不会导致细胞毒性有显著差异。1和2的IC50值在1 - 5 microM范围内。烷氧基膦酸酯1在抑制植入BALB/C小鼠体内的WEHI-3B和P388肿瘤生长方面非常有效。烷氧基和烷硫基膦酸酯1和2延长了携带L1210肿瘤的CD1小鼠的存活时间。在这些体外和体内研究中，ET-18-OMe的膦酸酯类似物的抗肿瘤活性与手性无关，这与先前对1-O-十六烷基-2-O-甲基-sn-甘油-3-磷酸胆碱对映体的研究一致。
