Synthesis of ether-linked analogues of lysophosphatidate and their effect on the proliferation of human epithelial cancer cells in vitro

To investigate whether lysophosphatidate analogues of alkyllsophospholipids were antiproliferative we synthesized three new, ether-linked analogues of lysophosphatidic acid and investigated their antiproliferative activity on epithelial cancer cell lines derived from different tissues. The antiproliferative effects of thee compounds on MCF-7 and T47D (breast), A549 and A427 (lung), A498 (kidney), SK-N-SH and SK-N-MC (neuroblastoma), and DU145 (prostate) cells were compared with the ability of 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine, the archetypic alkyllysophospholipid, to inhibit the proliferation of all the cell lines. 1-O-Hexadecyl-2-O-methyl-sn-glycero-3-phosphate and 4-thiohexadecyl-3(S)-O-methoxybutane-4-phosphate were unable to inhibit the proliferation of any of the cells to any degree, while slightly enhancing the proliferation of UD145 cells. In constrast 4-O-hexadecyl-3(S)-O-methoxybutanephosphonate was a potent antiproliferative agent that was on the whole more active than 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine. Since 1-Oleoyl-2-lyso-phosphatidate (LPA) was non-mitogenic in all the cell lines except the neuroblastoma line SK-N-SH, it is unlikely that the inhibition of cell proliferation by 4-O-hexadecyl-3-(S)-O-methoxybutanephosphonate was a consequence of perturbation of cellular response to the mitogenic effects of LPA.