Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine

Abstract

The following derivatives of 2''-deoxy-5''-O-1",3",2"-dioxaphosphacyclohex-2"-yluridine 2"-oxide were synthesized: 5-fluoro (4), 5"-(benzyloxy)-5-methyl (6), 5"-(benzyloxy)-5-fluoro (7), 5"-hydroxy-5-methyl (8), 5-fluoro-5"-hydroxy (9), 5",5"-difluoro-5-methyl (11) and 5,5",5"-trifluoro (12). Compounds 4, 9 and 12 were evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Compounds 12 was nearly as potent as 2''-deoxy-5-fluorouridine in its inhibitory effect on these cells (ID50 [50% inhibitory dose] = 0.003 and 0.001 .mu.g/ml, respectively). Compounds 4 and 9 were .apprx. 300 times less active than 12. None of the compounds was an inhibitor of the cell-free thymidylate synthetase, although their antiproliferative effects were achieved by the inhibition of this enzyme.