The cytotoxicity of [(N-alkyl-1H,3H-1-oxoisoindoline-5-yl-oxyl alkanoates and related benzamides in murine and human tissue cultured cell lines.
Substituted oxoisoindolines 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, 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 16 at both regulatory enzymes, i.e. PRPP amido transferase, IMP dehydrogenase and dihydrofolate reductase. The agent lowered d(GTP) and d(CTP) pool levels, further reducing DNA synthesis. DNA strand scission was evident after incubation with Compound 16 for 24 hr at 100 microM and some undefined interaction between the drug and the nucleoside bases appeared to occur, lowering DNA synthesis and causing cell death.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559-7360, USA.
Wyrick
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SD
Waller
C L
CL
D000582:Amidophosphoribosyltransferase / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D011687:Purines / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D011687:Purines; C057812:indoline; D007168:IMP Dehydrogenase; D000582:Amidophosphoribosyltransferase