Synthesis and biological properties of some cyclic phosphotriesters derived from 2'-deoxy-5-fluorouridine.
The following derivatives of 2'-deoxy-5'-O-1",3",2"-dioxaphosphacyclohex-2" -yluridine 2"-oxide have been synthesised: 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 have been evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Compound 12 was nearly as potent as 2'-deoxy-5-fluorouridine in its inhibitory effect on these cells (ID50 = 0.003 and 0.001 micrograms/mL, respectively). Compounds 4 and 9 were about 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.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis*; D001973:Bromodeoxyuridine / Q000633:toxicity; D003841:Deoxycytidine / Q000494:pharmacology; D003857:Deoxyuridine / Q000138:chemical synthesis* / Q000627:therapeutic use; D004351:Drug Resistance; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000494:pharmacology; D013938:Thymidine Monophosphate / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D007202:Indicators and Reagents; D009943:Organophosphorus Compounds; D003841:Deoxycytidine; D013938:Thymidine Monophosphate; D001973:Bromodeoxyuridine; D013936:Thymidine; D003857:Deoxyuridine