Nucleosides and nucleotides. 155. synthesis, antitumor effects, and possible enzymatic activation mechanism of 5′-phosphatidyl-2′-deoxy-2′-methylenecytidine (DMDC)

2′-Deoxy-2′-methylenecytidine (DMDC, 1) and its 5-fluoro congener (5-F-DMDC, 2), potent antitumor nucleosides developed by us, were efficiently converted to their 5′-phosphatidyl derivatives bearing palmitoyl residues (3 and 4, respectively) as novel antitumor phospholipids by phospholipase D-catalyzed trans-phosphatidylation. These phospholipids 3 and 4, administered i.p., remarkably prolonged the life-span of mice which were i.p.-inoculated with M5076 sarcoma, and the effects were clearly superior to that of DMDC. Compound 3 was a good substrate for phospholipase A2 from bovine pancreas as well as phospholipase D from Streptomyces, while it was slightly hydrolyzed by phospholipase C from Bacillus cereus.