Synthesis and antineoplastic activity of bis[[[(alkylamino)carbonyl]oxy]methyl]-substituted 3-pyrrolines as prodrugs of tumor inhibitory pyrrole bis(carbamates).
A series of bis[(carbamoyloxy)methyl]pyrrolines 2-4 were synthesized from either the appropriate alpha-silylated iminium salt, or an aziridine, or a 2H-azirine in a sequence involving 1,3-dipolar cycloaddition reactions. The antineoplastic activities of the pyrrolines were compared to the corresponding pyrroles. The C-2 gem-dimethyl-substituted pyrroline, 4, which cannot be converted to the pyrrole in vivo, was inactive. The activity of the 2-phenyl-substituted pyrrolines 3 was markedly dependent on the nature of the phenyl substituent, although the corresponding phenylpyrroles all showed comparable activity. The differences in the activities of the pyrrolines 3 may be due to the rate of metabolic conversion of the pyrroline to the pyrrole. Electron-withdrawing substituents on the phenyl ring appear to retard this process.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002219:Carbamates; D011758:Pyrroles