7-OXA[2.2.1]BICYCLOHEPTANE-2,3-DICARBOXYLIC ACID-DERIVATIVES AS PHOSPHATASE INHIBITORS

Cantharidin (1) as well as norcantharidin or endothall (2) have been d escribed to be inhibitors of protein phosphatase 2A, but were reported to be inactive as inhibitors of calcineurin. Using an HPLC-assay, we have discovered that 1 and 2 are inhibitors of calcineurin-dependent ( appKi = 10.8 and 3.26 mu M,respectively) dephosphorylation of a phosph opeptide derived from the RII subunit of c-AMP dependent kinase, HDLDV PIPGRFDRRVS(PO,)VAAE-OH (7), which is commonly used in calcineurin ass ays. The phosphatase inhibitor 6 also inhibits the production of IL-2 in Jurkat cells, a calcineurin dependent process, with IC50 = 4.7 mu M , indicating that some of the biological activity of this substance cl ass may be due to calcineurin inhibition, in addition to the establish ed PP2A inhibition. (C) 1997 Elsevier Science Ltd.