The cytotoxicity of heterocyclic thiosemicarbazones and their metal complexes on human and murine tissue culture cells.
Heterocyclic thiosemicarbazones, thioureas and 2-substituted pyridine N-oxides as well as representative nickel, cobalt and copper complexes were shown to be potent antineoplastic/cytotoxic agents. The cytotoxicity was demonstrated against single cell leukemia as well as cell lines derived from solid tissue (colon adenocarcinoma, HeLa, KB, skin, bronchogenic lung, bone osteosarcoma and glioma). In L1210 cells, DNA synthesis and subsequently RNA synthesis were particularly inhibited by the agents. IMP dehydrogenase activity and thus purine de novo synthesis was reduced significantly by the agents. Dihydrofolate reductase, ribonucleoside reductase, nucleoside kinase and DNA polymerase alpha activities were inhibited by the agents. d(NTP) pool levels were reduced by most of the agents. DNA strand scission was present with all of the derivatives; however, there was no evidence of intercalation, cross linking or alkylation/binding to bases of DNA. This new group of compounds may offer novel exploratory derivatives for future investigations in the treatment of cancer.
Hall
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IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27759.
Rajendran
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KG
West
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DX
Liberta
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AE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D008670:Metals / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors; D012334:RNA, Neoplasm / Q000378:metabolism; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008670:Metals; D009363:Neoplasm Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D012334:RNA, Neoplasm; D013882:Thiosemicarbazones; D004259:DNA-Directed DNA Polymerase