The cytotoxicity of N-substituted indazolones in murine and human tumor cells.
N-Substituted indazolones are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L1210, Tmolt3, colon adenocarcinoma and HeLa-S3. Selected agents were also active against the growth of KB, bronchogenic lung, osteosarcoma and glioma. The mode of action of the derivatives involves inhibition of de novo purine synthesis of L1210 cells, which reduces DNA and RNA syntheses. Agents lowered d(NTP) pools, further reducing DNA synthesis. DNA strand scission was evident after incubation with N-substituted indazolones for 24 h at 100 microM, lowering DNA synthesis and causing cell death.
Hall
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360.
Wong
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Hall
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Chen
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D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007191:Indazoles