Synthesis and evaluation of 3-halocyclophosphamides and analogous compounds as novel anticancer "pro-prodrugs".
3-Fluoro-, 3-chloro-, and 3-bromocyclophosphamide were prepared from the reaction of trifluoromethylhypofluorite, sodium hypochlorite, and bromine with the anticancer drug cyclophosphamide. Treatment of cis- and trans-4-phenylcyclophosphamide and 5,6-benzocyclophosphamide with sodium hypochlorite afforded cis- and trans-3-chloro-4-phenylcyclophosphamide and 3-chloro-5,6-benzocyclophosphamide, respectively. 31P-NMR spectroscopy was used to study the reactivity of these compounds: the fluoro derivative was reduced to cyclophosphamide on incubation with mouse liver slices, and the reactivity order for sulfhydryl-induced reduction of the 3-halocyclophosphamides was Br approximately equal to Cl much greater than F. Compared with the therapeutic efficacy of cyclophosphamide against L-1210 and P-388 cancers in mice, 3-fluoro- and 3-chlorocyclophosphamide were less active, although the fluoro derivative was more efficacious than the 3-chloro compound. The individual R and S enantiomers of 3-chlorocyclophosphamide, prepared from (S)- and (R)-cyclophosphamide, respectively, showed no significant difference in therapeutic activity in the P-388 test system.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D002626:Chemistry, Pharmaceutical; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D012995:Solubility
D000970:Antineoplastic Agents; D003520:Cyclophosphamide