SYNTHESIS OF ETHER-LINKED ANALOGS OF LYSOPHOSPHATIDATE AND THEIR EFFECT ON THE PROLIFERATION OF HUMAN EPITHELIAL CANCER-CELLS IN-VITRO

To investigate whether lysophosphatidate analogues of alkyllysophospho lipids were antiproliferative we synthesized three new ether-linked an alogues of lysophosphatidic acid and investigated their antiproliferat ive activity on epithelial cancer cancer cell lines derived from diffe rent tissues. The antiproliferative effects of the 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 t he ability of 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine, the a rchetypic alkyllysophospholipid, to inhibit the proliferation of all t he cell lines. 1-O-Hexadecyl-2-O-methyl-sn-glycero-3-phosphate and 4-t hiohexadecyl-3(S)-O-methoxybutane-4-phosphate were unable to inhibit t he proliferation of any of the cells to any degree, while slightly enh ancing the proliferation of DU145 cells. In contrast 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-mito genic 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.