New eremophilane sesquiterpenoid compounds, eremoxylarins A and B directly inhibit calcineurin in a manner independent of immunophilin

Abstract

In the course of our screening program for a new Ca2+-signal transduction inhibitor using the hypersensitive mutant strain of Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ), 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 mpk1Δ strain, specifically, compared to the cnb1Δ 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 μM with competitive inhibition in vitro. The eremophilane sesquiterpenoid structure in eremoxylarins could be a good leading compound for immunosuppressants and anti-allergy drugs. © Japan Antibiotics Research Association.