Cantharimides: A new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a d- or l-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC 50=3.22±0.7 μM; PP2A IC 50=0.81±0.1 μM and PP1 IC 50=2.82±0.6 μM; PP2A IC 50=1.35±0.3 μM, respectively) than norcantharidin (PP1 IC 50=5.31±0.76 μM; PP2A IC 50=2.9±1.04 μM) and essentially equipotent with cantharidin (PP1 IC 50=3.6±0.42 μM; PP2A IC 50=0.36±0.08 μM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A. A new series of cantharidin analogues, the cantharidiimides has been synthesised. Inhibition studies indicate that cantharidiimides possessing a d- or l-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC 50=3.22±0.7 μM; PP2A IC 50=0.81 μM and PP1 IC 50=2.82±0.6 μM; PP2A IC 50=1.35±0.3 μM, respectively) than norcantharidin (PP1 IC 50=5.31±0.76 μM; PP2A IC 50=2.9±1.04 μM) and essentially equipotent with cantharidin (PP1 IC 50=3.6±0.42 μM; PP2A IC 50=0.36±0.08 μM).