Synthesis and Antineoplastic Activity of Bisoxy>methyl>-Substituted 3-Pyrrolines as Prodrugs of Tumor Inhibitory Pyrrole Bis(carbamates)

Article abstract of DOI:10.1021/jm00161a019

A series of bis<(carbamoyloxy)methyl>pyrrolines 2-4 were synthesized from either the appropriate α-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 correspondingphenylpyrroles 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.