Phospholipase C inhibitors: a new class of cytotoxic agents.

A series of nitrocoumarin and nitrochromene derivatives have been pre- pared and shown to inhibit the phosphatidylinositol-specific phospholi- pase C(PLC) (IC 50 <10 μg/mL) isolated from human melanoma. The inhibi- tion of PLC by nitrocoumarin (4a) was time-dependent and irreversible. The inhibition of PLC was shown to interfere with inositide metabolism in whole cells (IC 50 =4 μg/mL) in a manner consistent with their pro- posed mode of activity. Finally, the compounds were shown to be growth inhibitory to cultured melanoma cells (ID 50 =2 μg/mL), suggesting that PLC may be an attractive new target for chemotherapeutic intervention