Toxic inhibition of smooth muscle contractility by plant‐derived sesquiterpenes caused by their chemically reactive α‐methylenebutyrolactone functions

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Abstract
1 Previous studies have shown that extracts of feverfew (Tanacetum parthenium) and parthenolide, a sesquiterpene α-methylenebutyrolactone obtained from it, inhibit smooth muscle contractility in a time-dependent, non-specific and irreversible manner. 2 The hypothesis that this toxic effect is due specifically to the presence in the sesquiterpene lactone of the potentially reactive α-methylene function was tested on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant-derived sesquiterpene lactones purified from yellow star thistle (Centaurea solstitialis): cynaropicrin (an α-methylenebutyrolactone) and solstitialin 13-acetate (lacking the α-methylene function), and (b) by chemically inactivating the α-methylene functions in cynaropicrin and parthenolide by reaction with cysteine. 3 The results show that the characteristic smooth muscle inhibitory profile is demonstrated by the two α-methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound lacking this functional group (solstitialin 13-acetate), or by those previously active compounds in which it has been inactivated with cysteine. 4 Thus the α-methylene function is critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones, which are natural products widely distributed in the Compositae family of flowering plants.