Synthesis and antineoplastic activity of bis[[[(alkylamino)carbonyl]oxy]methyl]-substituted 3-pyrrolines as prodrugs of tumor inhibitory pyrrole bis(carbamates).

Abstract

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.

• Authors: W K Anderson, A S Milowsky
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 29 Issue 11 Pg. 2241-9 (Nov 1986) ISSN: 0022-2623 [Print] United States
• PMID: 3783586 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Carbamates
• Pyrroles

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Carbamates (chemical synthesis, pharmacology)
• Leukemia P388 (drug therapy)
• Pyrroles (chemical synthesis, pharmacology)
• Structure-Activity Relationship