fraxetin and avarol

Semisynthesis of 13 new thio avarol derivatives (4-16) and in vitro evaluation on the photodamage response induced by UVB irradiation are described. Their ability to inhibit NF-kappaB activation and TNF-alpha generation in HaCaT cells as well as their antioxidant capacity in human neutrophils has also been studied. Among them we have identified two monophenyl thio avarol derivatives (4-5) lacking cytotoxicity which can be considered promising UVB photoprotective agents through the potent inhibition of NF-kappaB activation with a mild antioxidant pharmacological profile.

Topics: Antioxidants; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Humans; Magnetic Resonance Spectroscopy; Models, Chemical; Molecular Conformation; Neutrophils; NF-kappa B; Photochemistry; Reactive Oxygen Species; Sesquiterpenes; Tumor Necrosis Factor-alpha; Ultraviolet Rays

The synthesis and structure-activity relationships for a series of 14 new avarol derivatives as antioxidants and inhibitors of cell proliferation and PGE(2) generation in human keratinocytes are described. Compound 6 (thiosalicylic derivative) was the most potent inhibitor of superoxide generation in human neutrophils and also potently inhibited PGE(2) generation in the human keratinocyte HaCaT cell line. Compound 7(3'-methylaminoavarone) presented the best antiproliferative profile, by the inhibition of (3)H-thymidine incorporation in HaCaT cells, with potency similar to the reference compound anthralin. None of the avarol derivatives showed any sign of cytotoxicity measured as LDH release in treated keratinocytes. The potency and pharmacological profile of derivatives are also discussed.

Topics: Antioxidants; Dinoprostone; Free Radical Scavengers; Humans; Inhibitory Concentration 50; Italy; Keratinocytes; L-Lactate Dehydrogenase; Salicylates; Sesquiterpenes; Structure-Activity Relationship