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

• Published in: ChemMedChem 2008-12, Vol.3 (12), p.1878-1892
• Main Authors: Hill, Timothy A., Stewart, Scott G., Gordon, Christopher P., Ackland, Stephen P., Gilbert, Jayne, Sauer, Benjamin, Sakoff, Jennette A., McCluskey, Adam
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agents; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; cantharidin; Cantharidin - analogs & derivatives; Cantharidin - chemical synthesis; Cantharidin - pharmacology; Cell Line; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; inhibitors; Inhibitory Concentration 50; Mice; norcantharidin; Protein Phosphatase 1 - antagonists & inhibitors; Protein Phosphatase 1 - pharmacology; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - pharmacology; protein phosphatases 1 & 2A; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200800192

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. Norcantharidin analogues as potential anticancer agents: Aromatic substituted norcantharidin analogues were synthesised and evaluated for the protein phosphatase 1 and 2A and tumour cell line growth inhibition. While some derivatives possessed good inhibitory activity, bulky ortho substituents caused the aromatic ring to twist out of planarity of the amide functionality, leading to a loss of activity.