New eremophilane sesquiterpenoid compounds, eremoxylarins A and B directly inhibit calcineurin in a manner independent of immunophilin.
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.
Ogasawara
Yukiko
Y
Laboratory of Chemical Biology, Faculty of Agriculture, Iwate University, Iwate, Japan. kimurak@iwate-u.ac.jp
Yoshida
Jun
J
Shiono
Yoshihito
Y
Miyakawa
Tokichi
T
Kimura
Ken-ichi
K
D000595:Amino Acid Sequence; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020104:Immunophilins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D018021:Lithium Chloride / Q000494:pharmacology; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology*; D000081223:Polycyclic Sesquiterpenes; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D009281:Naphthalenes; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C018286:eremophilane compounds; D020104:Immunophilins; D018021:Lithium Chloride