ENANTIOSELECTIVE SYNTHESIS AND ANTIPROLIFERATIVE PROPERTIES OF AN ILMOFOSINE ANALOG, 2'-(TRIMETHYLAMMONIO)ETHYL 3-(HEXADECYLOXY)-2-(METHOXYMETHYL)PROPYL PHOSPHATE, ON EPITHELIAL CANCER CELL-GROWTH

An asymmetric synthesis of the 1-alkyloxy analog of the thioether phos phocholine ilmofosine (BM 41.440, rac-1), 2'-(trimethylammonio)ethyl 3 -(hexadecyloxy)-2-(methoxymethyl)propyl phosphate (2), is described. S tereoselectivity was obtained in an asymmetric hydroboration - oxidati on sequence carried out on a 2,2-disubstituted l-alkene, 3-(hexadecylo xy)-2-(methoxymethyl)-1-propene (9), which was prepared by starting wi th either ethyl acrylate or ethyl alpha-(hydroxymethyl)acrylate (3). ( IZ)- and (S)-2 and rac-1 were highly effective in inhibiting the proli feration of the breast adenocarcinoma cell line MCF-7 (IC50, 2 mu M), moderately effective against A549 (non-small-cell lung adenocarcinoma) (IC50, 8-10 mu M), and less effective against A427 (large cell lung c arcinoma) (IC50, similar to 20 mu M) The in vitro cytotoxicity against the three epithelial cancer cell lines was independent of the configu ration about C-2 of the glycerol backbone of 2 and was also not altere d by substitution of oxygen for sulfur in the sn-l ether linkage of il mofosine.