Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin): implications for the binding mode.

Cantharidin is well known as a potent serine/threonine protein phosphatase 1 and 2A (PP1 and PP2A) inhibitor, with less potent inhibitory activity for PP2B, which regulates T-cell proliferation. We synthesized and evaluated four optically pure stereoisomers of 1-substituted norcantharidin analogues. The absolute stereochemistry of each stereoisomer was determined based on X-ray crystal structure analysis. Remarkably, optically active cantharidin analogues having (1S)-configuration showed selective inhibition of PP2B, without inhibiting PP1 or PP2A.