Synthesis, chemistry, and antineoplastic activity of alpha-halopyridinium salts: potential pyridone prodrugs of acylated vinylogous carbinolamine tumor inhibitors.

Abstract

A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-1H-pyrrol izin-5- yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the alpha-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer composition, and ionic strength. The 4- and 5-pyrrolizinyl-2-halopyridinium iodides and the corresponding pyridones were evaluated against P388 lymphocytic leukemia in vivo. The alpha-fluoropyridinium compounds were active but the alpha-chloro compounds were not. This activity was correlated with the rates of hydrolysis of the alpha-halopyridinium compounds to the active pyridone. Compounds that were active in the P388 screen were evaluated in L1210 leukemia, M5076 carcinoma, and MX-1 mammary xenograft assays in mice.

• Authors: W K Anderson, D C Dean, T Endo
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 33 Issue 6 Pg. 1667-75 (Jun 1990) ISSN: 0022-2623 [Print] United States
• PMID: 2342060 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Prodrugs
• Pyridinium Compounds
• Pyridones
• Pyrroles

Topics

• Animals
• Antineoplastic Agents (chemical synthesis)
• Drug Screening Assays, Antitumor
• Hydrolysis
• Mice
• Prodrugs (chemical synthesis, therapeutic use)
• Pyridinium Compounds (chemical synthesis, therapeutic use)
• Pyridones (chemical synthesis, therapeutic use)
• Pyrroles (chemical synthesis, therapeutic use)