(o- and p-Nitrobenzyloxycarbonyl)-5-fluorouracil derivatives as potential conjugated bioreductive alkylating agents

• Published in: Journal of medicinal chemistry 1986-01, Vol.29 (1), p.84-89
• Main Authors: Lin, Tai Shun, Wang, Lin, Antonini, Ippolito, Cosby, Lucille A, Shiba, David A, Kirkpatrick, D. Lynn, Sartorelli, Alan C
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Chemical Phenomena; Chemistry; Exact sciences and technology; Fluorouracil - analogs & derivatives; Fluorouracil - chemical synthesis; Fluorouracil - therapeutic use; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Leukemia P388 - drug therapy; Mice; Neoplasms, Experimental - drug therapy; Organic chemistry; Oxygen - pharmacology; Preparations and properties; Sarcoma 180 - drug therapy; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00151a014

A series of (o- and p-nitrobenzyloxycarbonyl)-5-fluorouracil derivatives were synthesized by reacting o- or p-nitrobenzyl chloroformate with 5-fluorouracil in the presence of triethylamine in DMF or Me2SO. The reductive activation of these agents was hypothesized to generate a reactive methide and 5-fluorouracil, two components that are capable of synergistic interaction through complementary inhibition. Measurement of the surviving fractions of EMT6 tumor cells treated with these agents in culture under conditions of hypoxia and aerobiosis resulted in equal cell kill regardless of the state of oxygenation. One of the synthesized agents, 3-(p-nitrobenzyloxycarbonyl)-5-fluorouracil (4), appeared to be superior to 5-fluorouracil in prolonging the survival time of mice bearing intraperitoneal implants of the P388 leukemia and Sarcoma 180.