SYNTHESIS OF ALKYL CHAIN-MODIFIED ETHER LIPIDS AND EVALUATION OF THEIR IN-VITRO CYTOTOXICITY

A series of alkyl lysophospholipid (ALP) analogs of ET-18-OCH3 -octade cyl-2-O-methylrac-glycero-3-phosphocholine) containing modifications i n the long C-1 chain has been synthesized and evaluated in human tumor cell line cytotoxicity assays. The compounds have also been evaluated in platelet activating factor (PAF) receptor agonism and hemolysis te sts. Two modifications have been studied, introduction of a carbonyl g roup at different positions of the C-1 chain and branching of this cha in, in some compounds with incorporation of a phenyl group. Several co mpounds showed a cytotoxic potency comparable to that of the reference compound ET-18-OCH3, associated with reduced proaggregating and hemol ytic effects. The two enantiomers of -(7-oxooctadecyl)-2-O-methyl-rac- glycero-3-phospho choline (2) showed the same level of cytotoxicity or antiproliferative activity, with the PAF-agonistic effect confined to R-2. The very low stereoselectivity found in the in vitro cytotoxicit y confirms earlier results and indicates a lack of stereospecific inte ractions with a macromolecular target.