THE CYTOTOXICITY OF [N-ALKYL-1H, 3H-1-OXOISOINDOLIN-5-YL-OXY]ALKANOATES AND RELATED BENZAMIDES IN MURINE AND HUMAN TISSUE-CULTURED CELL-LINES

Substituted oxoisoindolines are effective cytotoxic agents, causing ce ll death in a number of tissue culture lines, e.g. L1210, Tmolt-3, and HeLa-S-3. In gene,al these agents were not active against the solid c ell growth, i.e. KB, skin, HCT-8 ileum, colon, bronchogenic lung, oste osarcoma and glioma; The mode of action of the derivatives involves in hibition of de novo purine synthesis of Tmolt-3 cells, which reduces D NA and RNA syntheses. Purine synthesis was reduced by compound 16 at b oth 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 evide nt after incubation with Compound 16 for 24 hr at 100 mu M and some un defined interaction between the dr-rig and the nucleoside bases appear ed to occur lowering DNA synthesis and musing cell death.