Norcantharidin analogues: PP1 and PP2A inhibition and potential therapeutic development

This study described in this work examines the potential for derivatives of the potent PP1 (IC50 9.0 µM) and PP2A (IC50 3.0µM) inhibitor, norcantharidin, the demethylated cantharidin analogue, and their protein phosphatase inhibition, namely PP1 and PP2A and their cytotoxicity across a range of human cancer cell lines. A variety of derivatives were examined, paying particular attention to modifications to the anhydride moiety. These included a series of ring opened and ring closed cantharimides, a series of α-hydroxylactams, a series of lactone analogues and derivatives, and a series of heteroatom substituted analogues. Of the analogues developed, the ring opened and ring closed cantharimides displayed moderate to excellent activity, in cases, an improvement over the lead compound norcantharidin was observed. The ring closed dodecyl-linked bis analogue (63) was the most potent analogue displaying µM potent cytoxicities against all the cell lines examined. Of the ring opened analogues, the morpholino analogues proved most active.