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

Cantharidin ( 1 ) and its derivatives are 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 IC 50 values of ∼15 and ∼3 μ m, respectively. Substituted aromatic amide analogues 45 , 48 , 49 , 52 , 53 , and 54 also displayed good PP1 and PP2A inhibition, with IC 50 values in the range of 15–10 μ M (PP1) and 11–5 μ 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 .