Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Bittman R,Byun HS,Mercier B,Salari Hdoi
10.1021/jm00029a016subject
Has Abstractpub_date
1994-02-04 00:00:00pages
425-30issue
3eissn
0022-2623issn
1520-4804journal_volume
37pub_type
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