Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition

Cantharidin (7) and its derivatives ore of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC50 values of similar to 15 and similar to 3 mu m, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC50 values in the range of 15-10 mu m(PP1) and 11-5 mu m (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.