Norcantharidin (3) is a potent PP1 (IC₅₀ = 9.0 ± 1.4 μM) and PP2A (IC₅₀ = 3.0 ± 0.4 μM) inhibitor with 3-fold PP2A selectivity and induces growth inhibition (GI₅₀ ~45 μM) across a range of human cancer cell lines including those of colorectal (HT29, SW480), breast (MCF-7), ovarian (A2780), lung (H460), skin (A431), prostate (DU145), neuroblastoma (BE2-C), and glioblastoma (SJ-G2) origin. Until now limited modifications to the parent compound have been tolerated. Surprisingly, simple heterocyclic half-acid norcantharidin analogues are more active than the original lead compound, with the morphilino-substituted (9) being a more potent (IC₅₀ = 2.8 ± 0.10 μM) and selective (4.6-fold) PP2A inhibitor with greater in vitro cytotoxicity (GI₅₀ ~9.6 μM) relative to norcantharidin. The analogous thiomorpholine-substituted (10) displays increased PP1 inhibition (IC₅₀ = 3.2 ± 0 μM) and reduced PP2A inhibition (IC₅₀ = 5.1 ± 0.41 μM), to norcantharidin. Synthesis of the analogous cantharidin analogue (19) with incorporation of the amine nitrogen into the heterocycle further increases PP1 (IC₅₀ = 5.9 ± 2.2 μM) and PP2A (IC₅₀ = 0.79 ± 0.1 μM) inhibition and cell cytotoxicity (GI₅₀ ~3.3 μM). These analogues represent the most potent cantharidin analogues thus reported.
Bioorganic and Medicinal Chemistry Letters Vol. 17, Issue 12, p. 3392-3397