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 microM 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.
MacLauchlin
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Division of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.
Hall
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Izydore
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D012313:RNA; D004247:DNA