Norcantharidin analogues: Synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition

Timothy A. Hill, Scott G. Stewart, Christopher P. Gordon, Stephen P. Ackland, Jayne Gilbert, Benjamin Sauer, Jennette A. Sakoff, Adam McCluskey

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)


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 IC50 values of ∼15 and ∼3 μm, 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 μm (PP1) and 11-5 μm (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.

Original languageEnglish
Pages (from-to)1878-1892
Number of pages15
Issue number12
Publication statusPublished - 15 Dec 2008
Externally publishedYes


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