Wedelolactone and coumestan derivatives as new antihepatotoxic and antiphlogistic principles.
For the study of structure-activity relationships, the antihepatotoxic wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan) and 6 coumestan derivatives were synthesized by the application of a modified method of Wanzlich. An evaluation of the biological characteristics of the synthetic compounds and acuminatin from Musa acuminata showed that most of the wedelolactone derivatives significantly protected primary cultured liver cells from the toxicity of CCl4, galactosamine (Galc), and phalloidin, and strongly inhibited the activity of 5-lipoxygenase in porcine leukocytes. The hepatocyte protective activity was dependent on the C-7 substitution with pharmacological efficacy decreasing in the following order: EtO greater than MeO greater than OH greater than CH3(CH2)9. In addition, a free OH at C-5 of the wedelolactone molecule was shown to be important in protecting hepatocytes from CCl4 and Galc damage. Similar observation regarding the effect of C-7 substitution in wedelolactone was obtained in the 5-lipoxygenase test. In general, an increase in the lipophilicity in ring A increased the inhibition of 5-lipoxygenase activity. The synthetic wedelolactone was also found to have stimulatory effect on the RNA synthesis in isolated nuclei from hepatocytes.
Wong
S M
SM
Institut für Pharmazeutische Biologie, Universität München, Fed. Rep. of Germany.
Antus
S
S
Gottsegen
A
A
Fessler
B
B
Rao
G S
GS
Sonnenbichler
J
J
Wagner
H
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis*; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D007962:Leukocytes / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010590:Phalloidine / Q000037:antagonists & inhibitors / Q000633:toxicity; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D013552:Swine
D000893:Anti-Inflammatory Agents; D003374:Coumarins; D016859:Lipoxygenase Inhibitors; C051122:wedelolactone; D010590:Phalloidine; D012313:RNA; D001091:Arachidonate Lipoxygenases; D000410:Alanine Transaminase