In the course of our screening program for a new Ca2+-signal transduction inhibitor using the hypersensitive mutant strain of Saccharomyces cerevisiae (zds1Delta erg3Delta pdr1Delta pdr3Delta), new eremophilane sesquiterpenoid compounds eremoxylarins A and B were found to restore the growth inhibition caused by the hyperactivated Ca2+-signal. These compounds showed lethal activity against the mpk1Delta strain, specifically, compared to the cnb1Delta strain, and ion-sensitive activity against the wild-type strain in the presence of LiCl, indicating that their molecular target might be the calcineurin pathway. They inhibited calcineurin directly without immunophilins at IC50=2.7 and 1.4 microM with competitive inhibition in vitro. The eremophilane sesquiterpenoid structure in eremoxylarins could be a good leading compound for immunosuppressants and anti-allergy drugs.
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