Synthesis, chemistry, and antineoplastic activity of alpha-halopyridinium salts: potential pyridone prodrugs of acylated vinylogous carbinolamine tumor inhibitors |
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Authors: | W K Anderson D C Dean T Endo |
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Institution: | Department of Medicinal Chemistry, School of Pharmacy, State University of New York, Buffalo 14260. |
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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. |
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