A number of naturally occurring polyacylated guaianolides, structurally related to thapsigargin ( 1), are demonstrated to be potent activators of rat peritoneal mast cells. In order to characterize the structural requirements necessary for possessing this effect, a number of analogues are prepared and the activities are tested. The potencies of the natural products were positively correlated with their k'-values, as established by reverse-phase HPLC. The positive correlation could be expanded to partly hydrolyzed or partly hydrogenated derivatives. In contrast, derivatives not possessing the vicinal TRANS-dihydroxy moiety found in thapsigargin ( 1) have lost the structural requirements necessary for potently inducing a histamine release. Thus, lipophilicity is only one of the factors of importance for potency, another is the presence of the vicinal TRANS-dihydroxy moiety. The potency of one of the naturally occurring guaianolides, thapsigargicin ( 2), was only poorly predicted by the correlation. The structure of thapsivillosin F, previously isolated from THAPSIA VILLOSA, was established by spectroscopy and partial synthesis.
The potencies of thapsigargin and analogues as activators of rat peritoneal mast cells. Publishing Authors By Initials
