FR235222, a Fungal Metabolite, is a Novel Immunosuppressant that Inhibits Mammalian Histone Deacetylase

摘要

Cyclosporin A and tacrolimus dramatically changed the field of clinical transplantations, and they are also prescribed or currently developed for various autoimmune diseases. They suppress acute allograft rejection effectively, but chronic allograft rejection is a matter of issue on transplantations even when treated with these drugs~1), and their dosages are restricted because of their toxicities at high doses. Thus, different effects or safer properties are desirable for the next generation of immunosuppressant drugs. Taking the fact that cyclosporin A and tacrolimus share its mechanism as calcineurin inhibitors into consideration, we screened inhibitors of T-cell activation from microbial products to seek for new immunosuppressants with different mechanism of action and found a potent HDAC (histone deacetylase) inhibitor, FR235222 (1, Fig. 1). The isolation and biological properties of 1 are reported in the preceding papers~2,3). Herein, structure determination of FR235222 including its absolute stereochemistry will be presented.