title: Synthesis of alkyl chain-modified ether lipids and evaluation of their in vitro cytotoxicity.
abstract: A series of alkyl lysophospholipid (ALP) analogs of ET-18-OCH3 (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) containing modifications in 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 tests. Two modifications have been studied, introduction of a carbonyl group at different positions of the C-1 chain and branching of this chain, in some compounds with incorporation of a phenyl group. Several compounds showed a cytotoxic potency comparable to that of the reference compound ET-18-OCH3, associated with reduced proaggregating and hemolytic effects. The two enantiomers of 1-O-(7-oxooctadecyl)-2-O-methyl-rac-glycero-3-phosphocholine (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 cytotoxicity confirms earlier results and indicates a lack of stereospecific interactions with a macromolecular target.
authors.affiliation: Research and Development, Laboratorios Menarini SA, Badalona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Fos
authors.forename: N
authors.initials: N
authors.lastname: Suesa
authors.forename: L
authors.initials: L
authors.lastname: Borras
authors.forename: C
authors.initials: C
authors.lastname: Lobato
authors.forename: P
authors.initials: P
authors.lastname: Banfi
authors.forename: R A
authors.initials: RA
authors.lastname: Gambetta
authors.forename: F
authors.initials: F
authors.lastname: Zunino
authors.forename: D
authors.initials: D
authors.lastname: Mauleón
authors.forename: G
authors.initials: G
authors.lastname: Carganico
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006131:Growth Inhibitors; D006461:Hemolysis; D006801:Humans; D066298:In Vitro Techniques; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000633:toxicity; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011817:Rabbits; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D006131:Growth Inhibitors; D008246:Lysophospholipids; D010972:Platelet Activating Factor