Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity Original Research Article

Simple modifications to the anhydride moiety of norcantharidin have lead to the development of a series of analogues displaying modest PP1 inhibition (low μM IC50s) comparable to that of norcantharidin (PP1 IC50 = 10.3 ± 1.37 μM). However, unlike norcantharidin, which is a potent inhibitor of PP2A (IC50 = 2.69 ± 1.37 μM), these analogues show reduced PP2A inhibitory action resulting in the development of selective PP1 inhibitory compounds. Data indicates that the introduction of two ortho-disposed substituents on an aromatic ring, or para-substituent favours PP1 inhibition over PP2A inhibition. Introduction of a p-morphilinoaniline substituent, 35, affords an inhibitor displaying PP1 IC50 = 6.5 ± 2.3 μM; and PP2A IC50 = 7.9 ± 0.82 μM (PP1/PP2A = 0.82); and a 2,4,6-trimethylaniline, 23, displaying PP1 IC50 = 48 ± 9; and PP2A IC5 85 ± 3 μM (PP1/PP2A = 0.56). The latter shows a 7-fold improvement in PP1 versus PP2A selectivity when compared with norcantharidin. Subsequent analysis of 23 and 35 as potential PP2B inhibitors revealed modest inhibition with IC50s of 89 ± 6 and 42 ± 3 μM, respectively, and returned with PP1/PP2B selectivities of 0.54 and 0.15. Thus, these analogues are the simplest and most selective PP1 inhibitors retaining potency reported to date.