New cytotoxic and antitumor agents. VII. Derivatives of 1-benzylidenisoindolin-3-one and 5,6-dihydro-8H-isoquinolo(2,3-a)phthalasin-5-one.

The in vitro cytotoxic effects on P388 leukemia cells of 19 derivatives and analogs of 1-benzylidenisoindolin-3-one, 5,6-dihydro-8H-isoquinolo(2,3-a)phthalasin-5-one and 4-benzyl-1,2-dihydrophthalasin-5-one were studied. The derivatives of the first group which preferentially inhibited uridine utilization were more effective. The cytotoxic effects of these substances depended on the quality of substituents, on the presence of a nitrogen atom in the 5-membered heterocycle of the molecule as well as on the spatial arrangement of the molecule. (Z)-narceine imide-N-oxide II and (Z)-3-(6-ethyl-2-methoxy-3,4-methylenedioxy) benzyliden-6,7-dimethoxy-isoindolin-3-one III were the most active agents, both of them causing a decrease in the proliferation rate of P388 cells. After its addition to the culture medium, compound III caused irreversible damages leading to death of the cells. The removal of the inhibitor did not lead to the repair of the damages either. Of the other two groups of substances, 5-hydroxy-3,4,12-trimethoxy-8-methyl-10,11-methylenedioxy-8H-isoquino lo (2,3-a)phthalasin (XVIII) had a marked inhibitory effect which, at concentrations of up to 25 micrograms ml-1, inhibited the proliferation rate of P388 cells.