Synthesis and cytotoxic action of 1-oxoalkyl and 1,2-dioxoalkyl-1,2,4-triazolidine-3,5-diones in murine and human tissue cultured cells.

1-Oxoalkyl and 1,2-dioxoalkyl-1,2,4-triazolidine-3.5-diones proved to be potent antineoplastic agents in mouse tumors and potent cytotoxic agents particularly against the growth of suspended tumor cells. The compounds with shorter substituents in position 1 or positions 1 and 2 afforded the better activity. In L1210 lymphoid leukemia cells DNA, RNA, and protein syntheses were inhibited at 100 mu M after 60 min. Multiple enzyme sites in nucleic acid metabolism were affected by the compounds. i.e. DNA polymerase alpha, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthetase, and nucleoside kinases. These effects of the agents are probably additive in bringing about inhibition of DNA synthesis and cell death.