TOXIC INHIBITION OF SMOOTH-MUSCLE CONTRACTILITY BY PLANT-DERIVED SESQUITERPENES CAUSED BY THEIR CHEMICALLY REACTIVE ALPHA-METHYLENEBUTYROLACTONE FUNCTIONS

1 Previous studies have shown that extracts of feverfew (Tanacetum par thenium) and parthenolide, a sesquiterpene alpha-methylenebutyrolacton e obtained from it, inhibit smooth muscle contractility in a time-depe ndent, non-specific and irreversible manner. 2 The hypothesis that thi s toxic effect is due specifically to the presence in the sesquiterpen e lactone of the potentially reactive alpha-methylene function was tes ted on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant-derived sesquiterpene lactones puri fied from yellow star thistle (Centaurea solstitialis): cynaropicrin ( an alpha-methylenebutyrolactone) and solstitialin 13-acetate (lacking the alpha-methylene function), and (b) by chemically inactivating the alpha-methylene functions in cynaropicrin and parthenolide by reaction with cysteine. 3 The results show that the characteristic smooth musc le inhibitory profile is demonstrated by the two alpha-methylenebutyro lactones (parthenolide and cynaropicrin), but not by the compound lack ing this functional group (solstitialin 13-acetate), or by those previ ously active compounds in which it has been inactivated with cysteine. 4 Thus the alpha-methylene function is critical for this aspect of th e toxic pharmacological profile of the sesquiterpene butyrolactones, w hich are natural products widely distributed in the Compositae family of flowering plants.