Abstract
Classical, antifolate inhibitors of thymidylate synthase often suffer from a number of potential disadvantages when used as antitumor agents. These include impaired uptake due to an alteration of the active transport system required for cellular uptake, as well as the formation of long acting, nonโeffluxing polyglutaโmates via folypolyglutamate synthetase, which are responsible for toxicity to normal cells. To overcome some of the disadvantages of classical thymidylate synthase inhibitors, there has been considerable interest in the synthesis and evaluation of nonclassical inhibitors, which could enter cells via passive diffusion and are not substrates for folypolyglutamate synthetase. A series of eight nonclassical 6โsubstituted 2โaminoโ4โoxoโpyrrolo[2,3โd]pyrimidines 2aโ2h were designed as potential inhibitors of thymidylate synthase. The synthesis of the target compounds 2aโ2h was achieved via regioselective iodination at the 6โposition of 5, palladiumโcatalyzed coupling with the appropriate phenylacetylenes, reduction of the C8โC9 triple bond followed by saponification. Preliminary biological results indicated that none of the target compounds showed inhibitory activities against thymidylate synthase from Escherichia coli, Lactobacillus casei, rat or human thymidylate synthase at the concentrations tested. None of the target compounds showed inhibitory activity against dihydrofolate reductase from Escherichia coli, Lactobacillus casei, rat or human at 3.0 ร 10^โ5^ M. However, 50% inhibition of dihydrofolate reductase from Pneumocystis carinii and from Toxoplasma gondii was achieved with compound 2d and with compound 2g at 3.0 ร 10^โ5^ M.