title: Synthesis of phosphocholine and quaternary amine ether lipids and evaluation of in vitro antineoplastic activity.
abstract: The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine). Structural modification of 1-(alkylamido)-, -(alkylthio)-, and -(alkyloxy)propyl backbones has provided further insight into the structure-activity relationships of these lipids. In this study, a long saturated C-1 chain and a three-carbon backbone with a single short C-2 substituent were preferred. At the positively charged nitrogen of phosphocholines, fewer than three substituents caused a significant loss of activity, and substituents larger than methyl decreased activity slightly. In the nonphosphorus compounds, many nitrogen heterocycles and also a sulfonium moiety were incorporated without changing the degree of activity; however, a thiazolium group decreased activity. The most active compound, 29 [N-[3-(hexadecyloxy)-2-methoxypropyl]-3-(hydroxymethyl)pyridinium bromide], was approximately twice as active as the reference standard, ET-18-OMe, in a trypan blue dye exclusion assay.
authors.affiliation: School of Pharmacy, Division of Medicinal Chemistry and Natural Products, University of North Carolina, Chapel Hill 27599.
authors.forename: S L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: F
authors.initials: F
authors.lastname: Gumus
authors.forename: C J
authors.initials: CJ
authors.lastname: Marasco
authors.forename: K L
authors.initials: KL
authors.lastname: Meyer
authors.forename: M
authors.initials: M
authors.lastname: Marx
authors.forename: C
authors.initials: C
authors.lastname: Piantadosi
authors.forename: M D
authors.initials: MD
authors.lastname: Layne
authors.forename: E J
authors.initials: EJ
authors.lastname: Modest
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D004987:Ethers / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008055:Lipids / Q000138:chemical synthesis* / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives*; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004987:Ethers; D008055:Lipids; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D010767:Phosphorylcholine; C082307:N-(3-(hexadecyloxy)-2-methoxypropyl)-3-(hydroxymethyl)pyridinium