The cytotoxicity of [(N-alkyl-1,3-dioxo-1H,3H-isoindolin-5-yl)oxy]-alkanoic acids in murine and human tissue cultured cell lines.
Substituted isoindoline-1,3-diones are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L1210, Tmolt-3, and HeLa-S3. In general these agents were not active against the solid cell growth, i.e. KB, skin, colon, HCT-8 ileum, colon, bronchogenic lung, osteosarcoma and glioma. The mode of action of the derivatives involves inhibition of de novo purine synthesis of Tmolt-3 cells, which reduces DNA and RNA syntheses. Purine synthesis was reduced by compound 4 at both regulatory enzymes, i.e. PRPP amido transferase and IMP dehydrogenase. The agent lowered d(GTP) pools, further reducing DNA synthesis. DNA strand scission was evident after incubation with Compound 4 for 24 hr 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, USA.
Wyrick
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D000582:Amidophosphoribosyltransferase / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D011687:Purines / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007211:Indoles; D011687:Purines; C057812:indoline; D004247:DNA; D007168:IMP Dehydrogenase; D000582:Amidophosphoribosyltransferase