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 l-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 l-octadecyl-2-acetoacetylglycerophosphoUpids (la—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 (le, IC50 value® 1.5μg/ml). Thus, alkylphospholipids possessing a decamethylene bridge and a variety of substituents at position 2 (lg—n) were synthesized. They showed potent inhibitory activity with IC50 values ranging from 0.4 to 1.9μg/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (la—n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), l-octadecyl-2-acetoacetyl-3-glyceryl ω-trimethylammoniodecyl phosphate (le) showed the most potent life-prolonging effect. The structureacdvity relationships are discussed. © 1989, The Pharmaceutical Society of Japan. All rights reserved.