Synthesis of 5'-thymidinyl bis(1-aziridinyl)phosphinates as antineoplastic agents.
Reaction of 3'-acetylthymidine with phosphorus oxychloride in trimethyl phosphate yielded the phosphorodichloridate 5, which was subsequently reacted with aziridine, or 2,2-dimethylaziridine to give compounds 6 and 7, respectively. The 2,2-dimethylaziridine derivative 7 was considerably more active than 6 against leukemia L1210 and P-388 in mice but less active than the previously synthesized, simpler phosphinate derivatives 2 and 3. It appears that the thymidine moiety did not enable these compounds to use the nucleoside transport mechanism of the cells and also failed to increase the selectivity of the 2,2-dimethylaziridine analogues by interference with their binding to cholinesterase. Compound 7 strongly inhibited horse serum cholinesterase, while 6 was inactive.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001388:Aziridines / Q000138:chemical synthesis* / Q000494:pharmacology; D001389:Azirines / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis; D006736:Horses; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D010720:Phosphines / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001388:Aziridines; D001389:Azirines; D002800:Cholinesterase Inhibitors; D010720:Phosphines