title: Synthesis and antitumor activity of new alkylphospholipids containing modifications of the phosphocholine moiety.
abstract: New antitumor alkylglycerophospholipids, in which primarily the phosphocholine moiety of the platelet activating factor (PAF) molecule was modified, were synthesized from 1-alkyl-2-substituted glycerols by introducing polar head phosphoryl groups having methylene bridges of various lengths (from 2 to 14 carbons). They were tested for PAF agonistic activity and antitumor properties. In a series of 1-octadecyl-2-acetoacetylglycerophospholipids (1a-f), an increase in the length of the methylene bridge separating the phosphate and trimethylammonio group in the polar head side chain at position 3 of the glycerol backbone resulted in a progressive decrease in PAF agonistic activity and a characteristic change in antitumor activity against human promyelocytic leukemia cells (HL-60). Maximal potency was obtained with the compound having a decamethylene bridge (1e, IC50 value = 1.5 microgram/ml). Thus, alkylphospholipids possessing a decamethylene bridge and a variety of substituents at position 2 (1g-n) were synthesized. They showed potent inhibitory activity with IC50 values ranging from 0.4 to 1.9 micrograms/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (1a--n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), 1-octadecyl-2-acetoacetyl-3-glyceryl omega-trimethylammoniodecyl phosphate (1e) showed the most potent life-prolonging effect. The structure-activity relationships are discussed.
authors.forename: K
authors.initials: K
authors.lastname: Ukawa
authors.forename: E
authors.initials: E
authors.lastname: Imamiya
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Mizuno
authors.forename: A
authors.initials: A
authors.lastname: Tasaka
authors.forename: Z
authors.initials: Z
authors.lastname: Terashita
authors.forename: T
authors.initials: T
authors.lastname: Okutani
authors.forename: H
authors.initials: H
authors.lastname: Nomura
authors.forename: T
authors.initials: T
authors.lastname: Kasukabe
authors.forename: M
authors.initials: M
authors.lastname: Hozumi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D010713:Phosphatidylcholines / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D010713:Phosphatidylcholines