Phospholipase C inhibitors: a new class of cytotoxic agents.
A series of nitrocoumarin and nitrochromene derivatives have been prepared and shown to inhibit the phosphatidylinositol-specific phospholipase C(PLC)(IC50 < 10 micrograms/mL) isolated from human melanoma. The inhibition of PLC by nitrocoumarin 4a was time-dependent and irreversible. The inhibition of PLC was shown to interfere with inositide metabolism in whole cells (IC50 = 4 micrograms/mL) in a manner consistent with their proposed mode of activity. Finally, the compounds were shown to be growth inhibitory to cultured melanoma cells (ID50 = 2 micrograms/mL), suggesting that PLC may be an attractive new target for chemotherapeutic intervention.
Cancer Research Group, DuPont Merck Pharmaceutical Company, Glenolden Laboratory, Pennsylvania 19036.
F W
FW
Perrella
S F
SF
Chen
D L
DL
Behrens
R F
RF
Kaltenbach
S P
SP
Seitz
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002867:Chromones / Q000138:chemical synthesis*; D003374:Coumarins / Q000138:chemical synthesis*; D006801:Humans; D008545:Melanoma / Q000201:enzymology; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D002867:Chromones; D003374:Coumarins; D010716:Phosphatidylinositols; D010738:Type C Phospholipases