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 alkyllysophospholipids 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 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 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 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-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.
Ashagbley
A
A
Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Canada.
Samadder
P
P
Bittman
R
R
Erukulla
R K
RK
Byun
H S
HS
Arthur
G
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D001943:Breast Neoplasms; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004987:Ethers; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000633:toxicity; D008297:Male; D009447:Neuroblastoma; D063065:Organophosphonates; D011471:Prostatic Neoplasms; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004987:Ethers; D008246:Lysophospholipids; D063065:Organophosphonates